title: Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene.
abstract: Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Muthuswamy
authors.forename: Riley
authors.initials: R
authors.lastname: Boland
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Smith
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Hulstrand
authors.forename: Hope
authors.initials: H
authors.lastname: Northrup
authors.forename: Matthew
authors.initials: M
authors.lastname: Hakeman
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dierdorff
authors.forename: Christina K
authors.initials: CK
authors.lastname: Yung
authors.forename: Abby
authors.initials: A
authors.lastname: Long
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Brouillette
authors.forename: Kit Sing
authors.initials: KS
authors.lastname: Au
authors.forename: Christina
authors.initials: C
authors.lastname: Gurnett
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Houston
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cornell
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
mesh_terms: D000818:Animals; D016764:Cell Polarity; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D053673:Glypicans / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D016135:Spinal Dysraphism / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D044465:White People / Q000235:genetics; D015027:Zebrafish
chemical_list: D053673:Glypicans