Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease

Hirschsprung disease (HD) has been described in association with microcepha ly, mental retardation and characteristic facial features, delineating a sy ndrome possibly caused by mutations localized at chromosome 2q22-q23. We ha ve analyzed a de novo translocation breakpoint at 2q22 in one patient prese nting with this syndrome, and identified a gene, SIP1, which is disrupted b y this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeod omain transcription factors. We determined the genomic structure and expres sion of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing ea rly truncation of the protein. SIP1, among other functions, seems to play c rucial roles in normal embryonic development of neural structures and neura l crest. Its deficiency, in altering function of the TGF beta /BMP/Smad-med iated signalling cascade, is consistent with some of the dysmorphic feature s observed in this syndrome, in particular the enteric nervous system defec t that underlies HD.