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ALX4 gain‐of‐function mutations in nonsyndromic craniosynostosis
Author(s) -
Yagnik Garima,
Ghuman Apar,
Kim Sundon,
Stevens Christina G.,
Kimonis Virginia,
Stoler Joan,
SanchezLara Pedro A.,
Bernstein Jonathan A.,
Naydenov Cyril,
Drissi Hicham,
Cunningham Michael L.,
Kim Jinoh,
Boyadjiev Simeon A.
Publication year - 2012
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.22166
Subject(s) - biology , craniosynostosis , genetics , nonsynonymous substitution , exon , proband , mutation , gene , genome
Abstract Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Nonsyndromic craniosynostosis (NSC) accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal‐suture‐involved nonsyndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual‐luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain‐of‐function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC. Hum Mutat 33:1626–1629, 2012. © 2012 Wiley Periodicals, Inc.