Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q12-q14), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.
Source/Description: A 195 bp EcoRI-SalI fragment 19ES was used as an hybridization probe. It derives from a cDNA for the gene IFNAR which encodes the human interferon alpha receptor (1) (GenBank Accession Number J03171), and contains upstream non-coding and coding sequences (amino-acids 1-39). Polymorphism: HindIII identifies a 5-allele polymorphism with bands at 11.8 kb (A1), 10.9 kb (A2), 9.3 kb (A3), 8.9 kb (A4), 8.1 kb (AS). Frequency: Estimated from 31 unrelated individuals: Al: 0.23 A2: 0.35 A3: 0.24 PIC = 0.71 A4: 0.10 A5: 0.08 Not Polymorphic For: MspI, PstI. Chromosomal Localization: The human IFNAR gene maps to 21q22.1 (2). Mendelian Inheritance: Co-dominant segregation of the HindIll RFLP was observed in a three-generation family in which 17 individuals were typed (11 informative meioses). Probe Availability: The probe will be submitted to the American Tissue Culture Collection (ATCC). Until it is available through the ATCC, it can be obtained from E.V.
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