Abstract:
BACKGROUND:Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings. METHODS AND RESULTS:Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary α(2)δ2 subunit of high voltage gated calcium channels. The expression of the α(2)δ2-L1040P mutant instead of α(2)δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca(V)2.2) and L (Ca(V)1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α(2)δ2-L1040P mutant was synthesised normally in oocyte but only the α(2)δ2-WT, and not the α(2)δ2-L1040P mutant, increased the expression of α(1B), the pore forming subunit of Ca(V)2.2, at the plasma membrane. The expression of α(2)δ2-WT with Ca(V)2.2 increased the surface expression of α(1B) 2.5-3 fold and accelerated current inactivation, whereas α(2)δ2-L1040P did not produce any of these effects. CONCLUSIONS:L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α(2)δ2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient α(2)δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α(2)δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.
journal_name
J Med Genetjournal_title
Journal of medical geneticsauthors
Edvardson S,Oz S,Abulhijaa FA,Taher FB,Shaag A,Zenvirt S,Dascal N,Elpeleg Odoi
10.1136/jmedgenet-2012-101223subject
Has Abstractpub_date
2013-02-01 00:00:00pages
118-23issue
2eissn
0022-2593issn
1468-6244pii
jmedgenet-2012-101223journal_volume
50pub_type
杂志文章abstract:BACKGROUND:Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmedgenet-2019-106108
更新日期:2020-03-01 00:00:00
abstract::A study of mutation, biological fitness, and patterns of family building in Huntington's chorea has been carried out, based on a previously reported population study of the disorder in South Wales. No unequivocal new mutation was identified among 101 kindreds containing 418 affected persons, which supports the extreme...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.20.1.12
更新日期:1983-02-01 00:00:00
abstract::The accidental discovery, in an inguinal hernia, of a male gonad in a 67-year-old woman is reported. The association of an unambiguous female phenotype with a purely male karyotype and a male gonad suggests the diagnosis of testicular feminisation. The differential diagnosis, particularly of testicular feminisation wi...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.15.3.229
更新日期:1978-06-01 00:00:00
abstract:BACKGROUND:The diagnosis of calpainopathy is obtained by identifying calpain-3 protein deficiency or CAPN3 gene mutations. However, in many patients with limb girdle muscular dystrophy type 2A (LGMD2A), the calpain-3 protein quantity is normal because loss-of-function mutations cause its enzymatic inactivation. The ide...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.2006.044859
更新日期:2007-01-01 00:00:00
abstract:INTRODUCTION:The Tousled-like kinases 1 and 2 (TLK1 and TLK2) are involved in many fundamental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with 'Mental Retardation Autosomal Dominant 57' (MRD57, MIM# 618050), a neurodevelopme...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmedgenet-2020-107281
更新日期:2020-12-15 00:00:00
abstract::A 10 1/2 year old female with skeletal abnormalities was referred for genetic consultation because of learning disabilities and a suggestion of 'Turner-like' stigmata. Cytogenetic analysis revealed a paracentric inversion of an X(q13.1q26.1) chromosome. ...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.22.2.140
更新日期:1985-04-01 00:00:00
abstract::Familial amyotrophic lateral sclerosis (FALS) has recently been shown to be linked to chromosome 21 markers in a subset of families. However, we were unable to show linkage between FALS and chromosome 21 markers which flank the putative FALS locus in UK families. ...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.30.4.318
更新日期:1993-04-01 00:00:00
abstract:INTRODUCTION:Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangemen...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.2003.015867
更新日期:2004-07-01 00:00:00
abstract::Cytological and cytogenetic studies were performed on nucleated fetal cells present in chorionic villus transport medium. The erythroblastic origin of these cells was shown. Fetal erythroblasts in spontaneous mitosis were frequently observed; chromosome counts were obtained from them but poor quality often prevented b...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.29.10.709
更新日期:1992-10-01 00:00:00
abstract:BACKGROUND:Deletions of chromosome 19 have rarely been reported, with the exception of some patients with deletion 19q13.2 and Blackfan-Diamond syndrome due to haploinsufficiency of the RPS19 gene. Such a paucity of patients might be due to the difficulty in detecting a small rearrangement on this chromosome that lacks...
journal_title:Journal of medical genetics
pub_type: 信件
doi:10.1136/jmg.2008.062034
更新日期:2009-09-01 00:00:00
abstract::The FKHL7 gene has been implicated in the pathogenesis of glaucoma/autosomal dominant iridogoniodysgenesis (IGDA) (IRID1). This has been supported by mutations in some glaucoma and IGDA patients and the development of anterior eye chamber anomalies in patients with 6p deletions affecting the 6p25 region. We report a c...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:
更新日期:1999-09-01 00:00:00
abstract:BACKGROUND:Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and ne...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmedgenet-2012-101212
更新日期:2012-12-01 00:00:00
abstract::An association between Gaucher disease and Parkinson disease has been demonstrated by the concurrence of Gaucher disease and parkinsonism in rare patients and the identification of glucocerebrosidase mutations in probands with sporadic Parkinson disease. Using a different and complementary approach, we describe 10 unr...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.2004.024455
更新日期:2004-12-01 00:00:00
abstract::In an attempt to relate the age at onset of Huntington's disease to parental factors, the effects of parental onset-age (Po) and the age of the transmitting parent at the birth of a subsequently affected child (Pc) have been examined in a sample of cases ascertained from Victorian kindreds. There was a significant pos...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.12.1.64
更新日期:1975-03-01 00:00:00
abstract::We report four patients with hypertrichosis cubiti who were referred for investigation of short stature. Two males, whose height was on and just below the 3rd centile respectively, were sporadic cases and two females with disproportionate short stature were mother and daughter. Radiological changes present in the fami...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.26.6.382
更新日期:1989-06-01 00:00:00
abstract::Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmedgenet-2017-105188
更新日期:2018-06-01 00:00:00
abstract:BACKGROUND:We have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part of a larger malformation syndrome, since both craniofacial and central nervous system changes were pre...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.38.6.369
更新日期:2001-06-01 00:00:00
abstract::We report three new mutations in the gene for aldolase B that are associated with hereditary fructose intolerance (HFI). Two nonsense mutations create opal termination codons: R3op (C-->T, Arg3-->ter, exon 2) was found in homozygous form in four affected members of a large consanguineous Turkish pedigree and R59op (C-...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.31.6.499
更新日期:1994-06-01 00:00:00
abstract::A genetic study has been performed on five adrenoleucodystrophy families using DNA probes from Xq28. Members of each family had previously been tested for carrier status using the biochemical assay for very long chain fatty acids (VLCFAs), but several persons at risk had equivocal results. DNA analysis with four DNA p...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.27.11.670
更新日期:1990-11-01 00:00:00
abstract::The association of maternal uniparental disomy for chromosome 7 and postnatal growth failure has been reported in four cases and suggests the presence of genomic imprinting of one or more growth related genes on chromosome 7. However, in the reported cases, the possibility of homozygosity for a recessive mutation coul...
journal_title:Journal of medical genetics
pub_type: 杂志文章,评审
doi:10.1136/jmg.32.11.871
更新日期:1995-11-01 00:00:00
abstract::Inherited optic neuropathies are a significant cause of childhood and adult blindness and dominant optic atrophy (DOA) is the most common form of autosomally inherited (non-glaucomatous) optic neuropathy. Patients with DOA present with an insidious onset of bilateral visual loss and they characteristically have tempor...
journal_title:Journal of medical genetics
pub_type: 杂志文章,评审
doi:10.1136/jmg.35.10.793
更新日期:1998-10-01 00:00:00
abstract::C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systemat...
journal_title:Journal of medical genetics
pub_type: 杂志文章,评审
doi:10.1136/jmedgenet-2017-104752
更新日期:2017-09-01 00:00:00
abstract::A Brazilian family of Italian descent is described in which the beta-thalassaemia gene is interacting with an alpha chain variant Hb Hasharon (alpha 47 Asp leads to His). One patient who was affected by homozygous beta 0-thalassaemia and heterozygous alpha Hasharon displayed the clinical picture of thalassaemia interm...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.19.6.437
更新日期:1982-12-01 00:00:00
abstract::Mitochondria play a central role in the secretion of insulin by pancreatic beta-cells, and pathogenic mutations of mitochondrial DNA (mtDNA) can cause diabetes. The aetiology of type 2 diabetes has a strong genetic component, raising the possibility that genetic variants of mtDNA alter the risk of developing the disor...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.2007.048876
更新日期:2007-06-01 00:00:00
abstract:BACKGROUND:A variety of abnormalities have been demonstrated at chromosome 11p15 in individuals with overgrowth and growth retardation. The identification of these abnormalities is clinically important but often technically difficult. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a ...
journal_title:Journal of medical genetics
pub_type: 信件
doi:10.1136/jmg.2007.053207
更新日期:2008-02-01 00:00:00
abstract::Linkage of the anonymous marker D3S2 at 3p21 has been shown in three British families with dominant dystrophic epidermolysis bullosa with a combined lod score of 6.75 at theta = 0. This locus is close to the collagen type VII locus implying that abnormalities of this gene cause dominant dystrophic epidermolysis bullos...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.29.6.381
更新日期:1992-06-01 00:00:00
abstract:BACKGROUND:Multiple genes have been provisionally associated with Alzheimer's disease, including the coding polymorphisms in exons 8 and 13 in the low density lipoprotein receptor gene (LDLR), situated on chromosome 19p13.2. METHODS:The sample groups consisted of 180 AD patients and 141 control spouses. We carried out...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.2004.024968
更新日期:2005-02-01 00:00:00
abstract::A 39 year old male with primary infertility was diagnosed as having Klinefelter syndrome by conventional cytogenetic analysis, which also showed an abnormal chromosome 12. Fluorescence in situ hybridisation (FISH) analysis of the aberrant chromosome using a 12 specific centromeric probe showed a break in the alphoid r...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.35.8.682
更新日期:1998-08-01 00:00:00
abstract:BACKGROUND:Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bo...
journal_title:Journal of medical genetics
pub_type: 信件
doi:10.1136/jmg.2008.065201
更新日期:2009-08-01 00:00:00
abstract::Fragile X syndrome is caused by mutations in the FMR1 gene and is one of the most frequent forms of inherited mental retardation in males. Postnatal and prenatal diagnosis of fragile X syndrome is feasible by direct DNA analysis. A new approach to prenatal diagnosis of fragile X syndrome in amniotic fluid cells is des...
journal_title:Journal of medical genetics
pub_type: 杂志文章
doi:10.1136/jmg.34.3.250
更新日期:1997-03-01 00:00:00