Spectrum of mutations and genotype - phenotype analysis in Currarino syndrome

The triad of a presacral tumour, sacral agenesis and anorectal malformation constitutes the Currarino syndrome which is caused by dorsal-ventral patte rning defects during embryonic development. The syndrome occurs in the majo rity of patients as an autosomal dominant trait associated with mutations i n the homeobox gene HLXB9 which encodes the nuclear protein HB9. However, g enotype-phenotype analyses have been performed only in a few families and t here are no reports about the specific impact of HLXB9 mutations on HB9 fun ction. We performed a mutational analysis in 72 individuals from nine famil ies with Currarino syndrome. We identified a total of five HLXB9 mutations, four novel and one known mutation, in four out of four families and one ou t of five sporadic cases. Highly variable phenotypes and a low penetrance w ith half of all carriers being clinically asymptomatic were found in three families, whereas affected members of one family showed almost identical ph enotypes. However, an obvious genotype-phenotype correlation was not found. While HLXB9 mutations were diagnosed in 23 patients, no mutation or microd eletion was detected in four sporadic patients with Currarino syndrome. The distribution pattern of here and previously reported HLXB9 mutations indic ates mutational predilection sites within exon I and the homeobox. Furtherm ore, sequence homology to Drosophila homeobox genes suggest that some of th ese mutations located within the homeobox may after the DNA-binding specifi city of HB9 while those in sequences homologous to a recently identified NL S motif of the human homeobox gene PDX-1 may impair nuclear translocation o f the mutated protein.