Unstable expansion of the CAG trinucleotide repeat in MAB21L1: report of asecond pedigree and effect on protein expression

MAB21L1, originally termed CAGR1, is the human homologue of the C elegans c ell fate determining gene mab21. MAB21L1, mapped to 13q13, contains a highl y polymorphic 5' untranslated CAG repeat that normally ranges from six to 3 1 triplets in length. A pedigree has been previously reported in which the repeat length is expanded to 45-50 triplets and is transmitted unstably bet ween generations; the expansion did not correlate to a clinical phenotype b ut did exhibit somatic mosaicism, We now report a second pedigree with an e xpanded and unstably transmitted MAB21L1 CAG repeat of similar length. The expansion is not clearly associated with a clinical phenotype, though the c omplexity of the pedigree renders any conclusion concerning phenotype-genot ype relationships speculative. The expansion did not result in decreased ex pression of MAB21L1 protein. The length,C-G rich composition, somatic mosai cism, and unstable transmission of the expanded CAG repeat in MAB21L1 resem ble the premutations observed in other genes, such as FMR1 and MDPK, in whi ch longer expanded repeats are associated with a clinical phenotype. This r aises the possibility that longer expansions in the MAB21L1 repeat may also be associated with a clinical phenotype.