title: KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome.
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.
authors: Service de Biochimie et Génétique, AP-HP, Hôpital H. Mondor - A. Chenevier, Créteil F-94000, France.
authors: Loïc
authors: L
authors: Drévillon
authors: André
authors: A
authors: Megarbane
authors: Bénédicte
authors: B
authors: Demeer
authors: Corine
authors: C
authors: Matar
authors: Paule
authors: P
authors: Benit
authors: Audrey
authors: A
authors: Briand-Suleau
authors: Virginie
authors: V
authors: Bodereau
authors: Jamal
authors: J
authors: Ghoumid
authors: Mayssa
authors: M
authors: Nasser
authors: Xavier
authors: X
authors: Decrouy
authors: Martine
authors: M
authors: Doco-Fenzy
authors: Pierre
authors: P
authors: Rustin
authors: Dominique
authors: D
authors: Gaillard
authors: Michel
authors: M
authors: Goossens
authors: Irina
authors: I
authors: Giurgea
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005602:France; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007493:Iraq; D008297:Male; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D011485:Protein Binding; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D000199:Actins; C503132:KIFBP protein, human; D009419:Nerve Tissue Proteins; D014404:Tubulin