Molecular Analyses in Families with Hunter Syndrome Indicate Unequal Male and Female Mutation Rates in the Iduronate-2-Sulfatase Gene

Molecular diagnosis for patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) has detected a spectrum of mutations including large deletions, intragenic rearrangements, recurrent nucleotide substitutions at CpG sites, and high proportion of novel point mutations in the X-linked iduronate-2-sulfatase (IDS) gene. The mutational heterogeneity and the X-linked inheritance make the IDS gene a good disease model for studying human germline mutations and underlying mechanisms. Pooling data from 135 MPS II families observed that 8% were sporadic cases from de novo maternal germline mutations and 92% were transmitted cases from carrier females. Haplotyping analysis on transmitted cases showed preference of germline mutations from maternal grandfather. Estimation of male-to-female ratio of mutation rates indicated a 3.76-to-10.5-fold higher mutation rate in males for mutations in the IDS gene. However, little is known on gender-specific mutation rate for different type of mutations in the IDS gene. A large-scale population based collaborative study to construct a database of detailed mutational composition and family pedigrees is needed to further characterize the mutation origin and male/female mutation rates in the IDS gene. This information will be helpful in genetic counseling and disease prevention and also gain insight into mutagenesis mechanisms for various types of mutations.