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1.
Am J Med Genet A ; 131(3): 249-54, 2004 Dec 15.
Article in English | MEDLINE | ID: mdl-15523628

ABSTRACT

A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.


Subject(s)
Founder Effect , Ophthalmoplegia/genetics , Spinocerebellar Degenerations/genetics , Base Sequence , DNA Primers , Female , Genes, Dominant , Humans , Male , Newfoundland and Labrador , Pedigree
2.
Am J Hum Genet ; 70(3): 763-9, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11774073

ABSTRACT

The hereditary spastic ataxias (HSA) are a group of clinically heterogeneous neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia. HSA was diagnosed in three unrelated autosomal dominant families from Newfoundland, who presented mainly with severe leg spasticity, dysarthria, dysphagia, and ocular-movement abnormalities. A genomewide scan was performed on one family, and linkage to a novel locus for HSA on chromosome 12p13, which contains the as-yet-unidentified gene locus SAX1, was identified. Fine mapping confirmed linkage in the two large families, and the third, smaller family showed LOD scores suggestive of linkage. Haplotype construction by use of 13 polymorphic markers revealed that all three families share a disease haplotype, which key recombinants and overlapping haplotypes refine to about 5 cM, flanked by markers D12S93 and GATA151H05. SAX1 is the first locus mapped for autosomal dominant HSA.


Subject(s)
Ataxia/genetics , Chromosomes, Human, Pair 12/genetics , Genes, Dominant/genetics , Ataxia/physiopathology , Chromosome Mapping , Female , Haplotypes/genetics , Humans , Leg/physiopathology , Lod Score , Male , Newfoundland and Labrador , Ocular Motility Disorders/genetics , Pedigree , Polymorphism, Genetic/genetics , Recombination, Genetic/genetics
3.
Nat Genet ; 29(2): 166-73, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11586298

ABSTRACT

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , GTP Phosphohydrolases/metabolism , Guanine Nucleotide Exchange Factors/genetics , Mutation , Amino Acid Sequence , Animals , Chromosome Mapping , Chromosomes, Human, Pair 2 , Female , Guanine Nucleotide Exchange Factors/chemistry , Humans , Male , Mice , Molecular Sequence Data , Polymorphism, Genetic , Sequence Homology, Amino Acid
4.
Can J Neurol Sci ; 28(1): 51-5, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11252295

ABSTRACT

BACKGROUND: The aim of the present study was to identify the mutations in the connexin 32 gene in French-Canadian families with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS: Molecular analysis was performed by nonisotopic single strand conformation polymorphism (SSCP) analysis and sequencing. Clinical evaluation was carried out according to the scale defined by the European Hereditary Motor and Sensory Neuropathy Consortium. RESULTS: In one family, the mutation Arg142Trp was located in the transmembrane domain III whereas, in four other families we identified a novel mutation (Ser26Trp) located in the transmembrane domain I of the connexin 32 gene. Haplotype analysis revealed that these four families are related and suggests a founder mutation. Sixteen patients from these four families were studied. As expected, all the affected males were more clinically affected than the females and all affected patients exhibited some electrophysiological characteristics of demyelination. CONCLUSION: Our study suggests that the Ser26Trp mutation may cause a primary demyelinating neuropathy that is not associated with a specific clinical phenotype. We also find evidence that the majority of kindreds share a common ancestor.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Connexins/genetics , Mutation/genetics , Adult , Canada , Charcot-Marie-Tooth Disease/pathology , Charcot-Marie-Tooth Disease/physiopathology , DNA/genetics , Demyelinating Diseases/pathology , Electrophysiology , Female , Haplotypes , Humans , Male , Middle Aged , Phenotype
5.
Ann Neurol ; 49(2): 267-71, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11220750

ABSTRACT

We describe a French amyotrophic lateral sclerosis (ALS) family with two distinct mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The D90A mutation has been well described and clearly shown to cause recessive ALS. In this family, affected individuals are heterozygous for the D90A mutation and also carry a single copy of a novel SOD1 mutation, D96N. We propose that in this family both mutations are required for the development of disease.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Genes, Recessive/genetics , Superoxide Dismutase/genetics , Adult , Female , Heterozygote , Humans , Male , Mutation/genetics , Pedigree , Polymorphism, Single-Stranded Conformational , Superoxide Dismutase-1
6.
Genomics ; 61(1): 1-4, 1999 Oct 01.
Article in English | MEDLINE | ID: mdl-10512674

ABSTRACT

Congenital hereditary endothelial dystrophy (CHED) is a corneal disorder that presents with diffuse bilateral corneal clouding. Vision may be severely impaired, and many patients require corneal transplantation. Both autosomal dominant (AD) and autosomal recessive (AR) forms of the disorder have been described. The gene responsible for AD CHED (HGMW-approved symbol CHED1) has been mapped to the pericentromeric region of chromosome 20. Investigating a large, consanguineous Irish pedigree with autosomal recessive CHED, we have previously excluded linkage to this AD CHED locus. We now describe a genome-wide search using homozygosity mapping and DNA pooling. Evidence of linkage to chromosome 20p was demonstrated with a maximum lod score of 9.30 at a recombination fraction of 0.0 using microsatellite marker D20S482. A region of homozygosity in all affected individuals was identified, narrowing the disease gene locus to an 8-cM region flanked by markers D20S113 and D20S882. This AR CHED (HGMW-approved symbol CHED2) disease gene locus is physically and genetically distinct from the AD CHED locus.


Subject(s)
Chromosomes, Human, Pair 20 , Corneal Dystrophies, Hereditary/genetics , Chromosome Mapping , Consanguinity , Endothelium, Corneal , Female , Genes, Recessive , Genetic Linkage , Homozygote , Humans , Male , Microsatellite Repeats , Pedigree
7.
Br J Ophthalmol ; 83(1): 115-9, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10209448

ABSTRACT

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.


Subject(s)
Corneal Dystrophies, Hereditary/genetics , Homozygote , Chromosome Mapping , Female , Humans , Male , Microsatellite Repeats , Pedigree , Polymorphism, Genetic
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