Recent progress in identification of the X-linked Spinal Muscular Atrophy (XLSMA) gene confirms a major disease locus between Xpl 1.3-Xpl 1.2

Abstract

We report our recent efforts toward the identification of the X-linked lethal infantile spinal muscular atrophy (XL-SMA) locus. Our collaborative group has previously described several families which display an X-linked recessive form of human motor neuron disease (AJHG. 61S. # 1554, 1997) Defining features include multiple generations of males with congenital onset of severe hypotonia, contracturcs and fractures; muscle biopsy indicative of neurogcnic atrophy; and autopsy indicating loss of anterior horn cells. The first family analyzed for linkage mapped to Xp 11.3-q11 2, and multipoint analysis refined this interval to a 11 cM region defined by DXS993-DXS991, with a maximum LOD score of 2.63 (Hum Molec Genet, 4(7): 1213-16,1995). Subsequently, seven unrelated families (six N. American, one European) have been identified and ascertained. These families were selected based on the above described inclusion criteria. Genomic DNA was prepared from blood and/or tissue specimens from affected and unaffected males, and obligate earner females, and analyzed using X-chromosome highly polymorphic DNA repeats Concordance analysis was used to define maternal meiotic recombination breakpoints surrounding a disease gene region, followed by multipoint linkage analysis using additional DNA markers. Results of these studies were interpreted using the LINKAGE and VITESSE programs, using the assumptions of a completely penetrant disease, with a gene frequency of 1 × 10−6. These combined results indicated that in addition to the first family reported above, four additional families have been linked to the same candidate disease gene interval, Xp11.3-q11 2. Multipoint linkage analysis has been completed for three of these four families and has refined this interval to a region defined by DXS991-DXS1003, with a maximum LOD score of 2.73 for these three families. The total additive LOD score for these three families, and the family previously published, is 5.36 at a Theta of 0.00 These results strongly support the existence of a major disease locus for XL-SMA between DXS 1003-DXS 991 (Xp 11.3-Xp 11.21) We are attempting to narrow the disease gene region through a search for recombinant individuals in each of the families using additional polymorphic markers We are also focusing our efforts on mutation screening of candidate disease genes within this region, particularly new candidates identified from a recently completed 1 1 mB transcript map of Xp11.3 Latest findings will be presented.