title: Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.
abstract: 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 delta 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 TGF beta/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.
authors.affiliation: INSERM U468 et service de Biochimie et Génétique, AP-HP, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
authors.forename: V
authors.initials: V
authors.lastname: Cacheux
authors.forename: F
authors.initials: F
authors.lastname: Dastot-Le Moal
authors.forename: H
authors.initials: H
authors.lastname: Kääriäinen
authors.forename: N
authors.initials: N
authors.lastname: Bondurand
authors.forename: R
authors.initials: R
authors.lastname: Rintala
authors.forename: B
authors.initials: B
authors.lastname: Boissier
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Mowat
authors.forename: M
authors.initials: M
authors.lastname: Goossens
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C108381:GEMIN2 protein, human; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors