Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss

Paraganglioma (PGL) is a rare disorder characterized by tumors of the head and neck region. Between 10% and 50% of cases of PGL are familial, and the disease is autosomal dominant and subject to age-dependent penetrance and i mprinting. The paraganglioma gene (PGLI) has been mapped to 11q22.3-q23, an d recently germline mutations in the SDHD gene have been identified. The SD HD region contains another gene, DPP2/TIMM8B, the homolog of which causes d ystonia and deafness seen in Mohr-Tranebjaerg syndrome. Using four PGL pedi grees, two of which exhibit coinheritance of PGL and sensorineural hearing loss or tinnitus, analysis of 14 microsatellite markers provided support fo r linkage to the PGLI locus. Sequence analysis identified novel mutations i n exon 1 and exon 3 of the SDHD gene, including a novel two base pair delet ion in exon 3 creating a premature stop codon at position 67; a novel three base pair deletion in exon 3 resulting in the loss of Tyr-93; a missense m utation in exon 3 resulting in the substitution of Leu-81 for Pro-81; and a novel G-to-C substitution in exon 1 resulting in the substitution of Met-1 for Ile-1. No base changes were detected in the DPP2/TIMM8B gene. There wa s no apparent loss of heterozygosity at the site of the SDHD mutations. How ever, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. This has not previous ly been shown for this disorder. The inheritance and expression of the SDHD gene is consistent with the PGLI gene being subject to genomic imprinting. (C) 2001 Wiley-Liss, Inc.