Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype.

Autosomal recessive spinal muscular atrophy (SMA) is classified, on the basis of age at onset and severity, into three types: type I, severe; type II, intermediate; and type III, mild. The critical region in 5q13 contains an inverted repeat harboring several genes, including the survival motor neuron (SMN) gene, the neuronal apoptosis inhibitory protein (NAIP) gene, and the p44 gene, which encodes a transcription-factor subunit. Deletion of NAIP and p44 is observed more often in severe SMA, but there is no evidence that these genes play a role in the pathology of the disease. In > 90% of all SMA patients, exons 7 and 8 of the telomeric SMN gene (SMNtel) are not detectable, and this is also observed in some normal siblings and parents. Point mutations and gene conversions in SMNtel suggest that it plays a major role in the disease. To define a correlation between genotype and phenotype, we mapped deletions, using pulsed-field gel electrophoresis. Surprisingly, our data show that mutations in SMA types II and III, previously classed as deletions, are in fact due to gene-conversion events in which SMNtel is replaced by its centromeric counterpart, SMNcen. This results in a greater number of SMNcen copies in type II and type III patients compared with type I patients and enables a genotype/phenotype correlation to be made. We also demonstrate individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explains why no consensus map of this region has been produced. This DNA variation may be due to a midisatellite repeat array, which would promote the observed high deletion and gene-conversion rate.

[1]  M. Kaufmann,et al.  Pulsed-field gel electrophoresis. , 1998, Methods in molecular medicine.

[2]  J. Melki,et al.  Spinal muscular atrophy. , 1997, Current opinion in neurology.

[3]  K. Davies,et al.  Gene conversion at the SMN locus in autosomal recessive spinal muscular atrophy does not predict a mild phenotype , 1997, Neuromuscular Disorders.

[4]  C. Ponting,et al.  Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? , 1997, Human molecular genetics.

[5]  J. Mendell,et al.  Deletion and conversion in spinal muscular atrophy patients: Is there a relationship to severity? , 1997, Annals of neurology.

[6]  A. Munnich,et al.  The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease. , 1997, American journal of human genetics.

[7]  M. Schwartz,et al.  Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy. , 1997, Human molecular genetics.

[8]  K. Davies,et al.  Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy. , 1996, Journal of medical genetics.

[9]  J. Melki,et al.  Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I. , 1996, Human molecular genetics.

[10]  K. Devriendt,et al.  Clinical and molecular genetic features of congenital spinal muscular atrophy , 1996, Annals of neurology.

[11]  B. Wirth,et al.  Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. , 1996, American journal of human genetics.

[12]  D. Parsons,et al.  An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. , 1996, Human molecular genetics.

[13]  J. D. den Dunnen,et al.  Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. , 1996, American journal of human genetics.

[14]  G. Dreyfuss,et al.  A novel nuclear structure containing the survival of motor neurons protein. , 1996, The EMBO journal.

[15]  K. Devriendt,et al.  Unusual molecular findings in autosomal recessive spinal muscular atrophy. , 1996, Journal of medical genetics.

[16]  A. Munnich,et al.  Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. , 1996, Journal of medical genetics.

[17]  T. Gilliam,et al.  Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. , 1996, Human molecular genetics.

[18]  K. Davies,et al.  Gene deletions in spinal muscular atrophy. , 1996, Journal of medical genetics.

[19]  E. Velasco,et al.  Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype. , 1996, Human molecular genetics.

[20]  A. Munnich,et al.  A frame–shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients , 1995, Nature Genetics.

[21]  H. Scheffer,et al.  Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. , 1995, American journal of human genetics.

[22]  B. Wirth,et al.  Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. , 1995, Human molecular genetics.

[23]  B. Wirth,et al.  Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. , 1995, Human molecular genetics.

[24]  K. Davies,et al.  Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13. , 1995, Genomics.

[25]  L. Kunkel,et al.  Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Osinga,et al.  PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy , 1995, The Lancet.

[27]  J. Carpten,et al.  Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays. , 1995, Genomics.

[28]  K. Davies,et al.  Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. , 1995, Human molecular genetics.

[29]  T. Crawford,et al.  The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy , 1995, Cell.

[30]  J. Weissenbach,et al.  Identification and characterization of a spinal muscular atrophy-determining gene , 1995, Cell.

[31]  K. Davies,et al.  Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13. , 1994, American journal of human genetics.

[32]  J. McPherson,et al.  Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy. , 1994, American journal of human genetics.

[33]  J. Carpten,et al.  A YAC contig of the region containing the spinal muscular atrophy gene (SMA): identification of an unstable region. , 1994, Genomics.

[34]  D. Le Paslier,et al.  De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. , 1994, Science.

[35]  J. Hoeijmakers,et al.  p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair. , 1994, The EMBO journal.

[36]  M. Leversha,et al.  A rearrangement on chromosome 5 of an expressed human beta-glucuronidase pseudogene. , 1994, Mammalian genome : official journal of the International Mammalian Genome Society.

[37]  A. Chapelle,et al.  Disease gene mapping in isolated human populations: the example of Finland. , 1993, Journal of medical genetics.

[38]  A. Monaco,et al.  A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13. , 1993, Human molecular genetics.

[39]  A. Grunn,et al.  Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T. Munsat,et al.  International SMA Consortium Meeting (26–28 June 1992, Bonn, Germany) , 1992, Neuromuscular Disorders.

[41]  A. Emery.  Clinical and genetic heterogeneity in spinal muscular atrophy—the multiple allele model , 1991, Neuromuscular Disorders.

[42]  M. Lathrop,et al.  Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14 , 1990, The Lancet.

[43]  T. Lehner,et al.  Genetic homogeneity between acute and chronic forms of spinal muscular atrophy , 1990, Nature.

[44]  M. Lathrop,et al.  Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q , 1990, Nature.

[45]  M. Leppert,et al.  Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2–13.3 , 1990, Nature.

[46]  A. Ruokonen,et al.  Prenatal diagnosis of single gene disorders in northern Finland. , 1990, Annals of medicine.

[47]  T. Strachan,et al.  Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21‐hydroxylase and complement C4 gene repeats in 21‐hydroxylase deficiency haplotypes. , 1989, The EMBO journal.

[48]  Y. Nakamura,et al.  Characterization of a human 'midisatellite' sequence. , 1987, Nucleic acids research.

[49]  V. Dubowitz.  Muscle disorders in childhood. , 1977, Israel journal of medical sciences.