Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus

被引:52
|
作者
Drielsma, Anais [1 ,2 ]
Jalas, Chaim [3 ]
Simonis, Nicolas [4 ]
Desir, Julie [1 ]
Simanovsky, Natalia [5 ]
Pirson, Isabelle [2 ]
Elpeleg, Orly [6 ]
Abramowicz, Marc [1 ]
Edvardson, Simon [6 ]
机构
[1] Univ Libre Bruxelles, Hop Erasme ULB, Dept Med Genet, B-1070 Brussels, Belgium
[2] Univ Libre Bruxelles, Inst Interdisciplinary Res IRIBHM, B-1070 Brussels, Belgium
[3] Bonei Olam Ctr Rare Jewish Dis, New York, NY USA
[4] Univ Libre Bruxelles, Bioinformat Genome & Networks BiGRe, B-1070 Brussels, Belgium
[5] Hadassah Hebrew Univ, Med Ctr, Dept Med Imaging, Jerusalem, Israel
[6] Hadassah Hebrew Univ, Med Ctr, Monique & Jacques Roboh Dept Genet Res, Jerusalem, Israel
关键词
PDZ DOMAINS; PROTEIN; STENOSIS; AQUEDUCT; SYLVIUS; IDENTIFICATION; OBSTRUCTION; PATHWAY; FAMILY;
D O I
10.1136/jmedgenet-2012-101190
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl-associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported. Methods We used homozygosity mapping and whole exome sequencing in two families with primary, non-syndromic congenital hydrocephalus from two different ethnic backgrounds. Results In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly-Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled. Conclusions Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein.
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收藏
页码:708 / 712
页数:5
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