Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems.

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development.

[1]  J. Osinga,et al.  A consanguineous family with Hirschsprung disease, microcephaly, and mental retardation (Goldberg-Shprintzen syndrome) , 1999, Journal of medical genetics.

[2]  T. Ueda,et al.  Embryogenesis of intramural ganglia of the gut and its relation to Hirschsprung's disease , 1967 .

[3]  G. Ferrero,et al.  Pachygyria and cerebellar hypoplasia in a patient with a 2q22‐q23 deletion that includes the ZFHX1B gene , 2004, American journal of medical genetics. Part A.

[4]  C. Cepko,et al.  Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis , 2000, Nature Genetics.

[5]  William B. Dobyns,et al.  G Protein-Coupled Receptor-Dependent Development of Human Frontal Cortex , 2004, Science.

[6]  G. Lathrop,et al.  Easy calculations of lod scores and genetic risks on small computers. , 1984, American journal of human genetics.

[7]  S. Züchner,et al.  Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. , 2003, American journal of human genetics.

[8]  A J Barkovich,et al.  Bilateral generalized polymicrogyria (BGP) , 2004, Neurology.

[9]  P. Barth,et al.  Disorders of Neuronal Migration , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[10]  R. Shprintzen,et al.  Hirschsprung megacolon and cleft palate in two sibs. , 1981, Journal of craniofacial genetics and developmental biology.

[11]  Lynne Regan,et al.  TPR proteins: the versatile helix. , 2003, Trends in biochemical sciences.

[12]  S. Shorvon,et al.  Polymicrogyria and absence of pineal gland due to PAX6 mutation , 2003, Annals of neurology.

[13]  F. Ciardo,et al.  Autosomal Recessive Polymicrogyria with Infantile Spasms and Limb Deformities , 2001, Neuropediatrics.

[14]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[15]  A. Rauch,et al.  "Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. , 2002, American journal of medical genetics.

[16]  E S Lander,et al.  Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. , 1987, Science.

[17]  N. Nomura,et al.  Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease , 2001, Nature Genetics.

[18]  A. Munnich,et al.  Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. , 2001, American journal of human genetics.

[19]  P. Barth,et al.  Parabiotic twin syndrome with topical isocortical disruption and gastroschisis , 2004, Acta Neuropathologica.

[20]  B. Kerr,et al.  Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. , 1998, Journal of medical genetics.

[21]  Jeanette C Papp,et al.  Detection and integration of genotyping errors in statistical genetics. , 2002, American journal of human genetics.

[22]  E. Brett,et al.  Unknown syndrome: Hirschsprung's disease, microcephaly, and iris coloboma: a new syndrome of defective neuronal migration. , 1988, Journal of medical genetics.