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Novel variants identified in methyl-CpG-binding domain genes in autistic individualsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter codi...
Source: Neurogenetics - November 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-ICEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report that Atp10a is biallelically expressed in both the newborn and adult brain, and Atp10a allelic expression is insensitive to deletion or mutation of the PWS imprinting center. The CpG island associated with Atp10a is hypomethylated, a result consistent with the notion that Atp10a is not an imprinted gene. Content Type Journal ArticleCategory ORIGINAL ARTICLEDOI 10.1007/s10048-009-0226-9Authors Amanda J. DuBose, University of Florida College of Medicine Department of Molecular Genetics and Microbiology Gainesville Florida 32610-0266 USAKaren A. Johnstone, Peninsula Medical School, University of Exeter Institut...
Source: Neurogenetics - November 5, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Isolated eyelid closure myotonia in two families with sodium channel myotoniaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe the first distinctive clinical genotype–phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype–phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients. Content Type Journal ArticleCategory SHORT COMMUNICATIONDOI 10.1007/s10048-009-0225-xAuthors B. C. Stunnenberg, Radboud University Nijmegen Medical Centre Department of Neurology, Neuromuscular Centre Nijmegen Reinier Po...
Source: Neurogenetics - October 29, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Suggestive evidence on chromosomes 2 and 19 for HTR1A-independent linkage of genes to major depressionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory LETTERDOI 10.1007/s10048-009-0222-0Authors Victor Abkevich, Myriad Genetics 320 Wakara Way Salt Lake City UT 84108 USAChris D. Neff, Myriad Genetics 320 Wakara Way Salt Lake City UT 84108 USAJennifer Potter, Myriad Genetics 320 Wakara Way Salt Lake City UT 84108 USARobin Riley, Myriad Genetics 320 Wakara Way Salt Lake City UT 84108 USADonna Shattuck, Myriad Genetics 320 Wakara Way Salt Lake City UT 84108 USADavid A. Katz, Abbott Laboratories 100 Abbott Park Road, R48B/AP4 Abbott Park IL 60064 USA Journal neurogeneticsOnline ISSN 1364-6753Print ISSN 1364-6745 (Source: Neurogenetics)
Source: Neurogenetics - October 8, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variantEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo m...
Source: Neurogenetics - October 6, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Acknowledgement to Referees 2008/2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory ACKNOWLEDGEMENT TO REFEREESDOI 10.1007/s10048-009-0221-1 Journal neurogeneticsOnline ISSN 1364-6753Print ISSN 1364-6745 Journal Volume Volume 10 Journal Issue Volume 10, Number 4 / October, 2009 (Source: Neurogenetics)
Source: Neurogenetics - September 30, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract We have identified a novel splice site mutation (IVS6-1G > A) in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. SAP102 is a member of the neuronal membrane-associated guanylate kinase protein subfamily comprising SAP97, postsynaptic density (PSD)95, and PSD93, which interacts with methyl-d-aspartate receptor and associated protein complexes at the postsynaptic density of excitatory synapses. DLG3 is the first mental retardation gene directly linked to glutamate recept...
Source: Neurogenetics - September 30, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A Copine family member, Cpne8, is a candidate quantitative trait gene for prion disease incubation time in mouseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we use the Northport heterogeneous stock of mice to reduce the size of a previously identified QTL on Mmu15 from approximately 25 to 1.2 cM. We further characterised the genes in this region and identify Cpne8, a member of the copine family, as the most promising candidate gene. We also show that Cpne8 mRNA is upregulated at the terminal stage of disease, supporting a role in prion disease. Applying these techniques to other loci will facilitate the identification of key pathways in prion disease pathogenesis. Content Type Journal ArticleCategory ORIGINAL ARTICLEDOI 10.1007/s10048-009-0219-8Authors...
Source: Neurogenetics - September 30, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Progressive retinal atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 geneEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Canine generalized progressive retinal atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 (CCDC66) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop ...
Source: Neurogenetics - September 24, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal modelsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory ErratumDOI 10.1007/s10048-009-0213-1Authors Alejandro Leal, Friedrich-Alexander University Institute of Human Genetics Schwabachanlage 10 91054 Erlangen GermanyKathrin Huehne, Friedrich-Alexander University Institute of Human Genetics Schwabachanlage 10 91054 Erlangen GermanyFinn Bauer, Friedrich-Alexander University Institute of Biochemistry Emil-Fischer-Zentrum, Fahrstraße 17 91054 Erlangen GermanyHeinrich Sticht, Friedrich-Alexander University Institute of Biochemistry Emil-Fischer-Zentrum, Fahrstraße 17 91054 Erlangen GermanyPhilipp Berger, Swiss Federal Institute of Technolog...
Source: Neurogenetics - September 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson’s disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostr...
Source: Neurogenetics - September 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Intratumoral patterns of clonal evolution in gliomasEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Few studies have explored the patterns of clonal evolution in gliomas. Here, we investigate the cytogenetic patterns of intratumoral clonal evolution of gliomas and their impact on tumor histopathology and patient survival. Cytogenetic analysis of 90 gliomas was performed in individual tumor cells (>200 cells/tumor) using multicolor (N = 16 probes) interphase—FISH. Overall, chromosome gains were more frequent than chromosome losses. Gains of chromosome 7 and/or EGFR amplification were detected in 91% of the cases, whereas del(9p21) (77%) and del(10q23) (78%) were the most frequent chromosome...
Source: Neurogenetics - September 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy c...
Source: Neurogenetics - September 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Periphilin is a novel interactor of synphilin-1, a protein implicated in Parkinson's diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein and its interactor synphilin-1 are major components of these inclusions. Rare mutations in the α-synuclein and synphilin-1 genes have been implicated in the pathogenesis of PD; however, the normal function of these proteins is far from being completely elucidated. We, thus, searched for novel synphilin-1-interacting proteins and deciphered periphilin as new interactor. Periphilin isoforms are involved in multiple cellular functions in viv...
Source: Neurogenetics - September 16, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST geneEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Bovine spinal dysmyelination (BSD) is a recessive congenital neurodegenerative disease in cattle (Bos taurus) characterized by pathological changes of the myelin sheaths in the spinal cord. The occurrence of BSD is a longstanding problem in the American Brown Swiss (ABS) breed and in several European cattle breeds upgraded with ABS. Here, we show that the disease locus on bovine chromosome 11 harbors the SPAST gene that, when mutated, is responsible for the human disorder hereditary spastic paraplegia (HSP). Initially, SPAST encoding Spastin was considered a less likely candidate gene for BSD since th...
Source: Neurogenetics - August 28, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Increased transcript diversity: novel splicing variants of Machado–Joseph Disease gene (ATXN3)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Machado–Joseph disease (MJD) is a late-onset neurodegenerative disorder that presents clinical heterogeneity not completely explained by its causative mutation. MJD is caused by an expansion of a CAG tract at exon 10 of the ATXN3 gene (14q32.1), which encodes for ataxin-3. The main goal of this study was to analyze the occurrence of alternative splicing at the ATXN3 gene, by sequencing a total of 415 cDNAs clones (from 20 MJD patients and 14 controls). Two novel exons are described for the ATXN3 gene. Fifty-six alternative splicing variants, generated by four types of splicing events, were observed...
Source: Neurogenetics - August 28, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Compound Charcot-Marie-Tooth disease may determine unusual and milder phenotypesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this report, we present a father and a daughter with a very mild and unusual disease that segregates with two mutations in PMP22 gene, the 17p11.2-p12 duplication and a Ser72Leu point mutation. We propose that the deleterious effects of each mutation are partially compensated by the functional effect of the other. Content Type Journal ArticleCategory SHORT COMMUNICATIONDOI 10.1007/s10048-009-0211-3Authors Silmara P. Gouvea, University of São Paulo Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto São Paulo BrazilVinícius H. S. Borghetti, University of São Paulo Departm...
Source: Neurogenetics - August 24, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Prader–Willi syndrome, Snord115, and Htr2c editingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory LETTER TO THE EDITORSDOI 10.1007/s10048-009-0209-xAuthors Heather Glatt-Deeley, University of Connecticut School of Medicine Department of Genetics and Developmental Biology 263 Farmington Ave Farmington CT 06030-3301 USADaria L. Bancescu, University of Connecticut School of Medicine Department of Genetics and Developmental Biology 263 Farmington Ave Farmington CT 06030-3301 USAMarc Lalande, University of Connecticut School of Medicine Department of Genetics and Developmental Biology 263 Farmington Ave Farmington CT 06030-3301 USA Journal neurogeneticsOnline ISSN 1364-6753Pri...
Source: Neurogenetics - August 3, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Sequence variation in SORL1 and dementia risk in SwedesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid β-amyloid1–42, tau levels, ...
Source: Neurogenetics - August 3, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Identification of CACNA1A large deletions in four patients with episodic ataxiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Episodic ataxia is an autosomal dominant ion channel disorder characterized by paroxysmal attacks of incoordination. Episodic ataxia type 2 (EA2) is caused by mutations in CACNA1A. EA2 mutations are mostly nonsense and sometimes missense mutations. However, in some typical EA2 families, CACNA1A sequencing does not detect any point mutation. Herein, we have designed a quantitative multiplex polymerase chain reaction of short fluorescent fragment test to screen the 50 exons of CACNA1A and investigated 27 probands referred for molecular diagnosis of EA2 who did not show any point mutation in CACNA1A. W...
Source: Neurogenetics - July 25, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Adenine nucleotide translocase is involved in a mitochondrial coupling defect in MFN2-related Charcot–Marie–Tooth type 2A diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Charcot–Marie–Tooth type 2A disease (CMT2A), a dominantly inherited peripheral neuropathy, is caused by mutations in MFN2, a mitochondrial fusion protein. Having previously demonstrated a mitochondrial coupling defect in CMT2A patients’ fibroblasts, we here investigate mitochondrial oxygen consumption and the expression of adenine nucleotide translocase (ANT) and uncoupling proteins from eight other patients with the disease. The mitochondrial uncoupling was associated with a higher respiratory rate, essentially involving complex II proteins. Furthermore, a twofold increase in the expression of...
Source: Neurogenetics - July 18, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Ataxia with oculomotor apraxia (AOA) type 2 (AOA2 MIM 606002) is a recessive subtype of AOA characterized by cerebellar atrophy, oculomotor apraxia, early loss of reflexes, and peripheral neuropathy. Various mutations either in homozygous or compound heterozygous condition were so far identified in the associated gene SETX (MIM 608465). SETX encodes a large protein called senataxin with a DNA-RNA helicase domain and a putative N-terminus protein interaction domain. Here, we report the identification of two novel homozygous mutations in SETX gene, c.340_342delCTT (p.L114Del) and c.1669C > T (p....
Source: Neurogenetics - July 11, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report a family with multiple schwannomas and meningiomas. A SMARCB1 germline mutation in exon 1 was identified. The mutation, c.92A>T (p.Glu31Val), occurs in a highly conserved amino acid in the SMARCB1 protein. In addition, in silico analysis demonstrated that the mutation disrupts the donor consensus sequence of exon 1. RNA studies verified the absence of mRNA transcribed by the mutant allele. This is the first report of a SMARCB1 germline mutation in a family with schwannomatosis characterized by the development of multiple meningiomas. Content Type Journal ArticleCategory ORIGINAL ARTICLEDOI 10.1007/s10048-...
Source: Neurogenetics - July 7, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorderEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Patients with autism spectrum disorder (ASD) frequently harbour chromosome rearrangements and segmental aneuploidies, which allow us to identify candidate genes. In a boy with mild facial dysmorphisms, speech delay and ASD, we reconstructed by karyotyping, FISH and SNP array-based segmental aneuploidy profiling a highly complex chromosomal rearrangement involving at least three breaks in chromosome 1 and seven breaks in chromosome 7. Chromosome banding revealed an inversion of region 7q32.1–7q35 on the derivative chromosome 7. FISH with region-specific BACs mapped both inversion breakpoints and re...
Source: Neurogenetics - July 7, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A modifier locus on chromosome 5 contributes to L1 cell adhesion molecule X-linked hydrocephalus in miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Humans with L1 cell adhesion molecule (L1CAM) mutations exhibit X-linked hydrocephalus, as well as other severe neurological disorders. L1-6D mutant mice, which are homozygous for a deletion that removes the sixth immunoglobulin-like domain of L1cam, seldom display hydrocephalus on the 129/Sv background. However, the same L1-6D mutation produces severe hydrocephalus on the C57BL/6J background. To begin to understand how L1cam deficiencies result in hydrocephalus and to identify modifier loci that contribute to X-linked hydrocephalus by genetically interacting with L1cam, we conducted a genome-wide scan...
Source: Neurogenetics - June 30, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

COL25A1 triggers and promotes Alzheimer’s disease-like pathology in vivoEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Collagen XXV alpha 1 (COL25A1) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer’s disease (AD) brains. COL25A1 alleles have been associated with increased risk for AD in a Swedish population. COL25A1 is specifically expressed in neurons and binds to aggregated Aβ in vitro. However, its contribution to the pathogenesis of AD and in vivo function are unknown. Here, we report that over-expression of COL25A1 in transgenic mice increases p35/p25 and β-site APP-cleaving enzyme 1 (BACE1) levels, facilitates intracellular aggregation and extracellular matrix depos...
Source: Neurogenetics - June 23, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Reduced levels of survival motor neuron protein leads to aberrant motoneuron growth in a Xenopus model of muscular atrophyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. The loss of function of the smn1 gene, the main supplier of survival motor neuron protein (SMN) protein in human, leads to reduced levels of SMN and eventually to SMA. Here, we ask if the amphibian Xenopus tropicalis can be a good model system to study SMA. Inhibition of the production of SMN using antisense morpholinos leads to caudal muscular atrophy in tadpoles. Of note, early developmental patterning of muscles and motor neurons is unaffected in this system as well as acet...
Source: Neurogenetics - June 11, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A novel variation in the Twinkle linker region causing late-onset dementiaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe five patients from two unrelated Alsatian families with the new R374W variation in the Twinkle linker region who progressively developed an autosomal dominant multisystem disorder with PEO, hearing loss, myopathy, dysphagia, dysphonia, sensory neuropathy, and late-onset dementia resembling Alzheimer’s disease. These observations demonstrate that Twinkle variations in the linker domain alter cerebral function and further implicate disrupted mitochondrial DNA integrity in the pathogenesis of dementia. Content Type Journal ArticleCategory ORIGINAL ARTICLEDOI 10.1007/s10048-009-0202-4Authors Andoni Echan...
Source: Neurogenetics - June 10, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

U1 snRNA mis-binding: a new cause of CMT1BEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report the molecular characterization of two splice mutations in two different French families affected with a late onset form of Charcot–Marie–Tooth disease type 1B (CMT1B), an autosomal dominant inherited disorder caused by mutations in the myelin protein zero gene. The first substitution, c.306G>A, located in exon 3, does not change the codon p.Val102Val but is co-transmitted with the disease in the first family. The second substitution, c.675+3dup, is an insertion of a T at position +3 of intron 5. To identify the functional impact of these nucleotide changes on splicing and because no RNA sample was avai...
Source: Neurogenetics - May 28, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

SCA27 caused by a chromosome translocation: further delineation of the phenotypeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report of a spinocerebellar ataxia (SCA)27 in a daughter and her mother whose karyotype is 46, XX t(5;13)(q31.2;q33.1). The translocation breakpoint is identical in both patients, disrupting the gene-encoding fibroblast growth factor 14 isoform b (FGF14-1b). Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation. FGF14-1b is the predominant isoform in brain, where it interacts with the voltage gated Na channel. Fgf14−/− mice develop ataxia and paroxysmal dyskinesia and have cognitive deficits. One missense and...
Source: Neurogenetics - May 27, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorderEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene in Xp22.13 have been associated with infantile spasms, early-onset intractable epilepsy, and a Rett syndrome (RTT)-like phenotype. Using array comparative genomic hybridization, we identified variable-sized microdeletions involving exons 1–4 of the CDKL5 gene in three females with early-onset seizures. Two of these deletions were flanked by Alu repetitive elements and may have resulted from either non-allelic homologous recombination or the microhomology-mediated Fork Stalling and Template Switching/Microhomology-Mediated Break-Induced Re...
Source: Neurogenetics - May 27, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). ...
Source: Neurogenetics - May 21, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystoniaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Leber hereditary optic neuropathy and dystonia (LDYT) is a mitochondrial disorder associated with variable combinations of vision loss and progressive generalized dystonia. LDYT is a unique oxidative phosphorylation disorder caused by mutations in mitochondrial ND6 or ND4 gene. In this paper, we describe a Chinese family with 18 LDYT patients. The comprehensive nucleotide sequence analysis of the entire mitochondrial genome using resequencing microarray revealed a mutation (mtND3*10197A (m.10197G>A)) substituting a threonine for a highly conserved alanine at codon 47 of MTND3 on the background of...
Source: Neurogenetics - May 21, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical managementEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract While Friedreich's ataxia (FRDA) and ataxia telangiectasia (AT) are known to be the two most frequent forms of autosomal recessive cerebellar ataxia (ARCA), knowledge on the other forms of ARCA has been obtained only recently, and they appear to be rarer. Little is known about the epidemiological features and the relative frequency of the ARCAs and only few data are available about the comparative features of ARCAs. We prospectively studied 102 suspected ARCA cases from Eastern France (including 95 from the Alsace region) between 2002 and 2008. The diagnostic procedure was based on a sequential stra...
Source: Neurogenetics - May 14, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3–q25.1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity in the lower limbs. They are clinically heterogeneous, and pure forms as well as complicated forms with other accompanying clinical findings are known. HSPs are also genetically heterogeneous. We performed clinical and genetic studies in a consanguineous family with five affected members. A genome scan using 405 microsatellite markers for eight members of the family identified candidate gene loci, and subsequent fine mapping in 16 members identified the gene locus responsible for the HSP. The clinical manifestations we...
Source: Neurogenetics - May 5, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral d...
Source: Neurogenetics - April 25, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Movement disorder and neuronal migration disorder due to ARFGEF2 mutationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype. The brain MRI shows bilateral hyperintensity of the putamen, BPNH, and generalized atrophy. Loss of ARFGEF2 function affects vesicle trafficking, proliferation/apoptosis, and neurotransmitter receptor function. This can explain BPNH and microcephaly. We hypothesize that the movement disorder and the preferential damage to the...
Source: Neurogenetics - April 22, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Recent origin and spread of a common Welsh MAPT splice mutation causing frontotemporal lobar degenerationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract IVS10+16C>T is the most prevalent mutation in the microtubule-associated protein tau gene (MAPT) causing frontotemporal lobar degeneration (FTLD) in populations of British descent. A highly conserved 17q21 haplotype was identified in IVS10+16C>T chromosomes from North Wales, Greater Manchester and the London areas of the UK, Australia, and the USA, suggesting the occurrence of a common founder effect. To test this hypothesis, the age of the mutation was estimated by parametric and Bayesian analysis of linkage disequilibrium's decay over generations, and the results were compared with historica...
Source: Neurogenetics - April 14, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

A novel de novo MFN2 mutation causing CMT2A with upper motor neuron signsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory Short CommunicationDOI 10.1007/s10048-009-0188-yAuthors S. Ajroud-Driss, Northwestern University Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine 710 N. Lake Shore Drive, 14th floor Abbott Hall #1426 Chicago IL 60611 USAF. Fecto, Northwestern University Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine 300E Superior St, Tarry 13-715 Chicago IL 60611 USAK. Ajroud, Northwestern University Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine 300E Superior St, Tarry 13-715 Chicago I...
Source: Neurogenetics - April 7, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract We studied a Malian family with parental consanguinity and two of eight siblings affected with late-childhood-onset progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel homozygous single-nucleotide variant in the NHLRC1 gene, c.560A>C, producing the missense change H187P. The changed amino acid is highly conserved, and the mutation impairs malin's ability to degrade laforin in vitro. Pathological evaluation showed manifestations of Lafora disease in the entire brain, with particularly severe involvement of the palli...
Source: Neurogenetics - March 26, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern SpainEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson’s disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD...
Source: Neurogenetics - March 24, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal modelsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association...
Source: Neurogenetics - March 17, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Ashkenazi Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuriesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract The LRRK2 G2019S mutation is a major genetic determinant of Parkinson’s disease (PD) across the world that occurs at an elevated frequency in Ashkenazi Jews. We determined the LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients, using 16 genetic markers. A single haplotype was detected in all mutation carriers, indicating that these individuals share a common founder. Using a maximum-likelihood method, we estimate that Ashkenazi Jews with G2019S share a common ancestor who lived ∼1,830 (95% CI 1,560–2,160) years ago, around the second centu...
Source: Neurogenetics - March 13, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emergingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report our linkage data on a family with late-infantile NCL and show that the disease in this family is due to a homozygous novel mutation in the most recently described NCL gene (MFSD8). We use clinical data from our patients and the few others that have previously been reported to delineate the phenotype associated with mutations in this gene. We conclude that the phenotype is fairly consistent, which is a helpful guide to clinicians as they decide on the most cost-effective molecular testing strategies for NCLs. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s10048-009-0185-1Authors M. A. Al...
Source: Neurogenetics - March 11, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

The impact of spermine synthase ( SMS ) mutations on brain morphologyEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Snyder–Robinson syndrome (SRS) is a form of X-linked mental retardation resulting from mutations in spermine synthase (SMS), which impact neurodevelopment and cognitive outcome. We obtained cerebral, cerebellum, hippocampus, and red nucleus volumes from two males with SRS and 24 age- and gender-matched typically developing controls using volumetric neuroimaging analyses. Total brain volume was enlarged in males with SRS while cerebellum, hippocampus, and red nucleus volumes tended to be reduced compared to controls. Mutations of the X chromosome may modulate the risk for mental retardation thr...
Source: Neurogenetics - March 11, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer’s diseaseEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer’s disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for m...
Source: Neurogenetics - March 7, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Molecular analysis of NPC1 and NPC2 gene in 34 Niemann–Pick C Italian Patients: identification and structural modeling of novel mutationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract Niemann–Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal–lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and i...
Source: Neurogenetics - February 28, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Abstract It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations...
Source: Neurogenetics - February 25, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Reply to the “Letter to the Editors” by Steven BuyskeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory Letter to the EditorsDOI 10.1007/s10048-009-0180-6Authors K. Abu-Elneel, University of California Santa Barbara Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology Santa Barbara CA 93106 USAT. Liu, University of California Santa Barbara Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology Santa Barbara CA 93106 USAF. S. Gazzaniga, University of California Santa Barbara Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology Santa Barbara CA 93106 USAY. Nishimura, Univer...
Source: Neurogenetics - February 24, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals

Robust quantification of the SMN gene copy number by real-time TaqMan PCREmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Content Type Journal ArticleCategory ErratumDOI 10.1007/s10048-009-0181-5Authors Ilsa Gómez-Curet, Alfred I. duPont Hospital for Children Nemours Biomedical Research P.O. Box 269 Wilmington DE 19899 USAKaryn G. Robinson, Alfred I. duPont Hospital for Children Nemours Biomedical Research P.O. Box 269 Wilmington DE 19899 USAVicky L. Funanage, Alfred I. duPont Hospital for Children Nemours Biomedical Research P.O. Box 269 Wilmington DE 19899 USAThomas O. Crawford, Johns Hopkins University Departments of Neurology and Pediatrics Baltimore MD USAMena Scavina, Alfred I. duPont Hospital for Children Nemours Biomedical Resear...
Source: Neurogenetics - February 24, 2009 Category: Genetics & Stem Cells Tags: neurogenetics Source Type: journals