Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease

Journal Article · Fri Nov 01 04:00:00 EST 1996 · American Journal of Human Genetics

OSTI ID:508224

Hahnen, E; Schoenling, J; Zerres, K ^[1]

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1. Univ. of Bonn (Germany); and others

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5{prime} end of the SMN genes, suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-simulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the {alpha}-globin cluster, and the polymerase {alpha} arrest sites. This may explain why independent hybrid SMN genes show identical sequences. 35 refs., 4 figs., 1 tab.

• OSTI ID: 508224
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 5 Vol. 59; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
BIOLOGICAL MARKERS
CENTROMERES
DNA HYBRIDIZATION
DNA SEQUENCING
DNA-CLONING
GENE MUTATIONS
GENE RECOMBINATION
GENES
GENETIC MAPPING
GENOTYPE
HEREDITARY DISEASES
MUSCLES
NERVE CELLS
NERVOUS SYSTEM DISEASES
PATIENTS
PHENOTYPE
POLYMERASE CHAIN REACTION
RECESSIVE MUTATIONS
STRUCTURE-ACTIVITY RELATIONSHIPS
TELOMERES