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Abstract

Objectives:

NOG is an antagonist to bone morphogenetic proteins and plays an important role in proper bone and joint development. Dominant mutations in NOG may lead to a series of symphalangism spectrum disorders. In this study, we aimed to identify the genetic cause and the pathogenic mechanism of an autosomal dominant disorder with cosegregating proximal symphalangism and conductive hearing impairment in a Chinese family.

Methods:

Mutation screening of NOG was performed in the affected family members by polymerase chain reaction (PCR) amplification and direct sequencing. Western blotting analysis of NOG was performed in the leukocyte samples of the family members.

Results:

A novel p.W150C heterozygous mutation in NOG was identified cosegregating with the proximal symphalangism disorder in the family. Western blotting analysis showed that the p.W150C mutation interferes with the dimerization of the mutant NOG.

Conclusions:

Our results agreed with previously published results of in vitro studies and suggested that impaired dimerization of mutant NOG is an important pathogenic mechanism for the NOG-related symphalangism spectrum disorder.

Keywords

conductive hearing impairment dimerization mutation proximal symphalangism

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References

Baldridge

Shchelochkov

Kelley

Lee

. Signaling pathways in human skeletal dysplasias. Annu Rev Genomics Hum Genet. 2010;11:189-217.

Marcelino

Sciortino

Romero

. Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci USA. 2001;98:11353-11358.

Brunet

Mcmahon

Harland

. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science. 1998;280:1455-1457.

Ganaha

Kaname

Akazawa

. Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism. J Hum Genet. 2015;60:27-34.

Brown

Kim

Petty

. Characterization of a stapes ankylosis family with a NOG mutation. Otol Neurotol. 2003;24:210-215.

Human Gene Mutation Database. http://www.hgmd.cf.ac.uk. Accessed April 6, 2015.

Smith

Knecht

Harland

. Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm. Nature. 1993;361:547-549.

Usami

Abe

Nishio

. Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis. Clin Genet. 2012;82:514-520.

Yang

Cao

Liu

. Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. J Hum Genet. 2008;53:368-374.

10.

Huang

. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am J Hum Genet. 2009;85:53-63.

11.

HLBI Exome Sequencing Project (ESP) Exome Variant Server. http://evs.gs.washington.edu/EVS/. Accessed April 6, 2015.

12.

ExAC Browser (Beta) | Exome Aggregation Consortium. http://exac.broadinstitute.org/. Accessed April 6, 2015.

13.

Groppe

Greenwald

Wiater

. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature. 2002;420:636-642.

14.

Lehmann

Seemann

Silan

. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet. 2007;81:388-396.

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