DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).

Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.

[1]  J. Schulz,et al.  Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2 , 2004, Nature Genetics.

[2]  A Hofman,et al.  Genetic epidemiology of amyotrophic lateral sclerosis , 2003, Clinical genetics.

[3]  J. Mendell,et al.  Separable Roles for rent1/hUpf1 in Altered Splicing and Decay of Nonsense Transcripts , 2002, Science.

[4]  H. Hartung,et al.  Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? , 2002, Brain : a journal of neurology.

[5]  E. Bertini,et al.  Novel locus for autosomal dominant pure hereditary spastic paraplegia (SPG19) maps to chromosome 9q33–q34 , 2002, Annals of neurology.

[6]  B. Vogelstein,et al.  Phenotypic analysis of hMSH2 mutations in mouse cells carrying human chromosomes. , 2001, Cancer research.

[7]  M. Pericak-Vance,et al.  The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis , 2001, Nature Genetics.

[8]  T. Gibson,et al.  The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin , 2001, Nature Genetics.

[9]  S. Sugano,et al.  Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene , 2001, Nature Genetics.

[10]  T. Wienker,et al.  Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1 , 2001, Nature Genetics.

[11]  N. Tanner,et al.  DExD/H box RNA helicases: from generic motors to specific dissociation functions. , 2001, Molecular cell.

[12]  M. Mann,et al.  A Functional Interaction between the Survival Motor Neuron Complex and RNA Polymerase II , 2001, The Journal of cell biology.

[13]  S. Hadano,et al.  A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 , 2001, Nature Genetics.

[14]  K. Fischbeck,et al.  A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4 ) localizes to a 500-kb interval on chromosome 9q34 , 2000, Neurogenetics.

[15]  G. Meister,et al.  Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. , 2000, Human molecular genetics.

[16]  M. Brasch,et al.  Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation? , 2000, Human molecular genetics.

[17]  James R. Eshleman,et al.  Conversion of diploidy to haploidy , 2000, Nature.

[18]  Yanfa Yan,et al.  Alloys: Atomic structure of the quasicrystal Al72Ni20Co8 , 2000, Nature.

[19]  B. Crain,et al.  Autosomal dominant juvenile amyotrophic lateral sclerosis. , 1999, Brain : a journal of neurology.

[20]  L. Maquat,et al.  A mutated human homologue to yeast Upf1 protein has a dominant-negative effect on the decay of nonsense-containing mRNAs in mammalian cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Koenig,et al.  Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, γ‐globulin, and α‐fetoprotein , 1998 .

[22]  B. Crain,et al.  Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. , 1998, American journal of human genetics.

[23]  A. Pardee,et al.  Association of the mammalian helicase MAH with the pre-mRNA splicing complex. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Harding,et al.  Disorders of the motor neuron , 1994 .

[25]  A. Harding,et al.  Disorders of the motor neurone. , 1994, Bailliere's clinical neurology.

[26]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[27]  W G Alvord,et al.  Familial Amyotrophic Lateral Sclerosis, 1850-1989: A Statistical Analysis of the World Literature , 1991, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[28]  D. Silberberg,et al.  NERVE CONDUCTION AND OTHER STUDIES IN FAMILIES WITH CHARCOT-MARIE-TOOTH DISEASE. , 1964, Brain : a journal of neurology.