KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome

Hum Mol Genet. 2013 Jun 15;22(12):2387-99. doi: 10.1093/hmg/ddt083. Epub 2013 Feb 19.

Abstract

Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR). In 2005, homozygosity mapping in a large consanguineous family identified KIAA1279 as the disease-causing gene. KIAA1279 encodes KIF-binding protein (KBP), whose function is incompletely understood. Studies have identified either the mitochondria or the cytoskeleton as the site of KBP localization and interactions. To better delineate the KIAA1279-related clinical spectrum and the molecular mechanisms involved in GOSHS, we studied five new patients from three different families. The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function. Despite the absence of functional KBP, respiratory chain complex activity in patient fibroblasts was normal. KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton. KBP expression directly affected neurite growth in a neuron-like cell line (human neuroblastoma SH-SY5Y), in keeping with the central (polymicrogyria) and enteric (HSCR) neuronal developmental defects seen in GOSHS patients. The KBP interactions with actin filaments and microtubules (MTs) demonstrated in our study constitute the first evidence that an actin MT cross-link protein is involved in neuronal development in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Adolescent
  • Adult
  • Child
  • Craniofacial Abnormalities / genetics
  • Craniofacial Abnormalities / metabolism*
  • Female
  • France
  • Hirschsprung Disease / genetics
  • Hirschsprung Disease / metabolism*
  • Humans
  • Infant
  • Iraq
  • Male
  • Microtubules / genetics
  • Microtubules / metabolism*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Pedigree
  • Protein Binding
  • Tubulin / genetics
  • Tubulin / metabolism
  • White People / genetics

Substances

  • Actins
  • KIFBP protein, human
  • Nerve Tissue Proteins
  • Tubulin

Supplementary concepts

  • Goldberg-Shprintzen megacolon syndrome