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.

Figure 1

Schematic representation of the structural organization of SIP1 and of the positions of the identified mutations. Three functional domains (SBD, HD, and N- and C-ZF) and six identified mutations are given, with patient numbers.

Figure 2

Facial features of patients. Patients 6, 7, 8, and 11, at age 6, 7, 18, and 1 year(s), respectively. They demonstrate hypertelorism (in all cases), prognathism (in all cases), a low nasal root (in the cases of patients 6, 7, and 11), absence of the internal part of the eyebrows (in all cases), and strabismus (in the case of patient 11). Patients 6 and 7 underwent surgical correction of strabismus at age 3 years.

Figure 3

Expression patterns of ZFHX1B. A, Autoradiograph showing hybridization with a 685-bp ZFHX1B cDNA against a Multiple Tissue Expression Array mRNA dot blot. The order and arrangement of applied samples are given in panel B. C, Autoradiographs of northern blots hybridized with a 4.1-kb ZFHX1B full-length cDNA (containing all exons) and a 2.0-kb human β-actin cDNA as a control: lane 1, brain; lane 2, heart; lane 3, skeletal muscle; lane 4, colon; lane 5, thymus; lane 6, spleen; lane 7, kidney; lane 8, liver; lane 9, small intestine; lane 10, placenta; lane 11, lung; and lane 12, peripheral blood leukocytes.