A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element

Cristina M. Justice, Jinoh Kim, Sun Don Kim, Kyunhgho Kim, Garima Yagnik, Araceli Cuellar, Blake Carrington, Chung Ling Lu, Raman Sood, Simeon Boyd, Alexander F. Wilson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Craniosynostosis presents either as a nonsyndromic congenital anomaly or as a finding in nearly 200 genetic syndromes. Our previous genome-wide association study of sagittal nonsyndromic craniosynostosis identified associations with variants downstream from BMP2 and intronic in BBS9. Because no coding variants in BMP2 were identified, we hypothesized that conserved non-coding regulatory elements may alter BMP2 expression. In order to identify and characterize noncoding regulatory elements near BMP2, two conserved noncoding regions near the associated region on chromosome 20 were tested for regulatory activity with a Renilla luciferase assay. For a 711 base pair noncoding fragment encompassing the most strongly associated variant, rs1884302, the luciferase assay showed that the risk allele (C) of rs1884302 drives higher expression of the reporter than the common allele (T). When this same DNA fragment was tested in zebrafish transgenesis studies, a strikingly different expression pattern of the green fluorescent reporter was observed depending on whether the transgenic fish had the risk (C) or the common (T) allele at rs1884302. The in vitro results suggest that altered BMP2 regulatory function at rs1884302 may contribute to the etiology of sagittal nonsyndromic craniosynostosis. The in vivo results indicate that differences in regulatory activity depend on the presence of a C or T allele at rs1884302.

Original languageEnglish (US)
Pages (from-to)2893-2897
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number11
DOIs
StatePublished - Nov 1 2017

Fingerprint

Craniosynostoses
Alleles
Renilla Luciferases
Chromosomes, Human, Pair 20
Gene Transfer Techniques
Genome-Wide Association Study
Zebrafish
Luciferases
Base Pairing
Fishes
DNA

Keywords

  • BBS9
  • BMP signaling
  • BMP2
  • craniofacial development
  • craniosynostosis
  • enhancer

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. / Justice, Cristina M.; Kim, Jinoh; Kim, Sun Don; Kim, Kyunhgho; Yagnik, Garima; Cuellar, Araceli; Carrington, Blake; Lu, Chung Ling; Sood, Raman; Boyd, Simeon; Wilson, Alexander F.

In: American Journal of Medical Genetics, Part A, Vol. 173, No. 11, 01.11.2017, p. 2893-2897.

Research output: Contribution to journalArticle

Justice, CM, Kim, J, Kim, SD, Kim, K, Yagnik, G, Cuellar, A, Carrington, B, Lu, CL, Sood, R, Boyd, S & Wilson, AF 2017, 'A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element', American Journal of Medical Genetics, Part A, vol. 173, no. 11, pp. 2893-2897. https://doi.org/10.1002/ajmg.a.38392
Justice, Cristina M. ; Kim, Jinoh ; Kim, Sun Don ; Kim, Kyunhgho ; Yagnik, Garima ; Cuellar, Araceli ; Carrington, Blake ; Lu, Chung Ling ; Sood, Raman ; Boyd, Simeon ; Wilson, Alexander F. / A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. In: American Journal of Medical Genetics, Part A. 2017 ; Vol. 173, No. 11. pp. 2893-2897.
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