Nonsense and Frameshift Mutations in ZFHX1B, Encoding Smad-Interacting Protein 1, Cause a Complex Developmental Disorder with a Great Variety of Clinical Features

Abstract

Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor development, epilepsy, microcephaly, distinct facial features, and/or congenital heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX1B deficiency, except that they did not have HSCR. The results showed the previously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a single-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178delTT resulting in 727fs754X)-newly identified in the other three. All mutations occurred in one allele and were de novo events. These results demonstrate that ZFHX1B deficiency is an autosomal dominant complex developmental disorder and that individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels.

Interaction between Smad-interacting Protein-1 and the Corepressor C-terminal Binding Protein Is Dispensable for Transcriptional Repression of E-cadherin

“…In addition, SIP1 was identified in two independent large scale screens to identify genes relevant to cancer (31,32). Moreover, many mutations in SIP1, the majority of which lead to truncation of the protein, have recently been reported to cause congenital defects sometimes associated with Hirschsprung's disease (33)(34)(35)(36)(37)(38). Therefore, in addition to the study of the function of SIP1 in vivo in multiple biological and pathological processes, the elucidation of the mechanism of action of SIP1, preferably at the level of important target genes such as E-cadherin, remains crucial.…”

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

“…3,4 In 2002 Zweier et al 5 further delineated the phenotype of MWS with or without HSCR, invariably characterized by ZEB2 gene defects, and proposed that the condition be named Mowat-Wilson syndrome. More than 300 patients have been reported so far [6][7][8][9][10][11][12][13][14][15][16][17] (additional reviewed articles are listed in Supplementary File S1 online).…”

Complementary expression pattern of Zfhx1 genes Sip1 and δEF1 in the mouse embryo and their genetic interaction revealed by compound mutants

“…␦EF1 is required for proper development of facial bones (Takagi et al, 1998), and Sip1 activity is important for migration of the cephalic neural crest that colonizes the first branchial arch, the precursor of the maxillary and mandibular processes ( Van de Putte et al, 2003). In human, Sip1 heterozygosity causes Mowat-Wilson syndrome, which involves facial dysmorphism, such as a wide eye distance and wide nasal bridge Yamada et al, 2001). These earlier observations may suggest an additive nature for the function of Sip1 and ␦EF1, although they are expressed in different domains of the maxillary mesenchyme (Fig.…”