Human Molecular Genetics, 2001, Vol. 10, No. 14 1503-1510
© 2001 Oxford University Press
Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease
INSERM U468 et service de Biochimie et Génétique, AP-HP, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France, 1Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland, 2Helsinki University Children’s Hospital, Helsinki, Finland, 3Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia and 4Department of Medical Genetics, Sydney Children’s Hospital, Randwick, and School of Paediatrics, University of New South Wales, Sydney, Australia
Hirschsprung disease (HD) has been described in association with microcephaly, mental retardation and characteristic facial features, delineating a syndrome possibly caused by mutations localized at chromosome 2q22–q23. We have analyzed a de novo translocation breakpoint at 2q22 in one patient presenting with this syndrome, and identified a gene, SIP1, which is disrupted by this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the 
EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors. We determined the genomic structure and expression of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein. SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest. Its deficiency, in altering function of the TGFß/BMP/Smad-mediated signalling cascade, is consistent with some of the dysmorphic features observed in this syndrome, in particular the enteric nervous system defect that underlies HD.
+ To whom correspondence should be addressed. Tel: +33 1 49 81 28 61; Fax: +33 1 48 99 33 45; Email: michel.goossens@im3.inserm.frThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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