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Rare LRP6 Variants Identified in Spina Bifida Patients
Author(s) -
Lei Yunping,
Fathe Kristin,
McCartney Danielle,
Zhu Huiping,
Yang Wei,
Ross M. Elizabeth,
Shaw Gary M.,
Finnell Richard H.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22750
Subject(s) - lrp6 , biology , wnt signaling pathway , frizzled , neural tube , missense mutation , genetics , microbiology and biotechnology , signal transduction , phenotype , embryo , gene
Several single‐nucleotide variants ( SNV s) in low‐density lipoprotein receptor‐related protein 6 ( Lrp6 ) cause neural tube defects ( NTD s) in mice. We therefore examined LRP6 in 192 unrelated infants from C alifornia with the NTD , spina bifida, and found four heterozygous missense SNV s, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like C rooked tail and R ingleschwanz mouse variants, the p. T yr544 C ys L rp6 protein failed to bind the chaperone protein mesoderm development and impaired L rp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p. T yr544 C ys L rp6 variant downregulated canonical W nt signaling in a T op F lash luciferase reporter in vitro assay. In contrast, three L rp6 mutants (p. A la3 V al, p. T yr544 C ys, and p. A rg1574 L eu) increased noncanonical W nt/planar cell polarity ( PCP ) signaling in an A p1‐luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTD s, whereas L rp6 modulation of W nt/ PCP signaling would be more essential than its canonical pathway role in neural tube closure.