Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease caused by mutations in the NF1 gene. The mutation rate of NF1 is one of the highest known for human genes and the mutational analysis has revealed a wide variety of changes, a significant proportion of which affect normal pre-mRNA splicing. Here, we describe two truncating mutations in exon 37 of NF1, the recurrent c.6792C>A and the novel c.6799C>T change, that occur in cis and segregate with NF1 in a large family. The double mutation induces defective splicing of exon 37 and thus, we performed quantitative comparisons of transcripts harboring single (c.6792C>G or c.6792C>A) and double (c.6792C>A and c.6799C>T) mutations to assess their effects on exon 37 splicing. Skipping of exon 37 was greater and there were fewer mutant full-length transcripts in samples with the double mutation than in those carrying single mutations. Thus, the combination of the c.6792C>A and c.6799C>T mutations augmented exon 37 skipping. These findings suggest that, in addition to the previously described exonic splicing enhancer in the c.6791_6795 region, c.6799 lies within an additional regulatory element that influences the splicing of exon 37.

The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor.

Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity.