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Proc Natl Acad Sci U S A. February 15, 2011; 108 (7): 2915-20.

Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.

Fakhro KA , Choi M , Ware SM , Belmont JW , Towbin JA , Lifton RP , Khokha MK , Brueckner M .

Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 × 10(-4)). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P < 10(-6)). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning.

PubMed ID: 21282601
PMC ID: PMC3041108
Article link: Proc Natl Acad Sci U S A.
Grant support: R01DE018824 NIDCR NIH HHS, R01DE18825 NIDCR NIH HHS, R01HD045789 NICHD NIH HHSHoward Hughes Medical Institute

Genes referenced: aldh1a1 ccbl1 cryzl1 dnah9 galnt11 gdf7 greb1 grik1 ift88 igfbp5 laptm5 lrrc8a myh6 nek2 nup188 pdgfc pitx2 rho rock2 rpsa runx2 smarcal1 tgfbr2.2 tpk1 trat1
Antibodies referenced:
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