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A ZEBRAFISH MODEL FOR GOLDBERG‐SHPRINTZEN SYNDROME
Author(s) -
Shepherd Iain,
Delalande JeanMarie,
de Graaff Esther,
Brooks Alice,
Alves Moreira,
Eggen Bart,
Hofstra Robert
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1314-c
Subject(s) - zebrafish , biology , microcephaly , morpholino , model organism , phenotype , subtelomere , genetics , disease , neuroscience , gene , pathology , medicine , telomere
The enteric nervous system is the largest most complicated subdivision of the peripheral nervous system. We have established the zebrafish as a model system to investigate the genetic basis of ENS development and to functionally investigate human disease genes that effect ENS development. Goldberg‐Shprintzen syndrome (GOSHS) is a congenital disorder characterized by Hirschprung disease, mental retardation, microcephaly, bilateral generalized polymicrogyria as well as facial dysmorphism. GOSHS has recently been linked to recessive mutations in a novel gene KIAA1279 about which nothing is functionally known. We have cloned the zebrafish orthologue and knocked‐down its expression using anti‐sense oligonucleotides. We find that the pattern of expression and function of KIAA1279 is conserved between humans and zebrafish. To gain insights into the molecular mechanism that underlies the GOSH disease phenotypes we have undertaken a yeast 2 hybrid screen. Data from this screen has led us to propose a model that disruption of KIAA1279 results in abnormal mitochondria localization and abnormal neuronal microtubule dynamics. This disruption leads to cell death in KIAA1279 expressing cells. This model is consistent with both the zebrafish morphant results and pathology reports form GOSHS patients.