Association of AHSG with alopecia and mental retardation (APMR) syndrome
- 684 Downloads
Alopecia with mental retardation syndrome (APMR) is a very rare autosomal recessive condition that is associated with total or partial absence of hair from the scalp and other parts of the body as well as variable intellectual disability. Here we present whole-exome sequencing results of a large consanguineous family segregating APMR syndrome with seven affected family members. Our study revealed a novel predicted pathogenic, homozygous missense mutation in the AHSG (OMIM 138680) gene (AHSG: NM_001622:exon7:c.950G>A:p.Arg317His). The variant is predicted to affect a region of the protein required for protein processing and disrupts a phosphorylation motif. In addition, the altered protein migrates with an aberrant size relative to healthy individuals. Consistent with the phenotype, AHSG maps within APMR linkage region 1 (APMR 1) as reported before, and falls within runs of homozygosity (ROH). Previous families with APMR syndrome have been studied through linkage analyses and the linkage resolution did not allow pointing out to a single gene candidate. Our study is the first report to identify a homozygous missense mutation for APMR syndrome through whole-exome sequencing.
KeywordsBone Morphogenetic Protein Signaling Phosphorylation Motif Exome Sequencing Project Exome Aggregation Consortium Advanced Sleep Phase Syndrome
We thank O. Dagan-Rosenfeld, A. Lipchik, A. Narasimha and H. Rost for many helpful discussions and input regarding the manuscript. M.R.S is supported by a grant from the Swiss National Science Foundation (SNSF). Work in the Snyder lab is supported by NIH Grants to M.P.S. (1P50HG00773501 and 8U54DK10255602). We thank the Stanford Center for Genomics and Personalized Medicine for their sequencing services.
Compliance with ethical standards
Conflict of interest
M. P. S. is a cofounder of Personalis and a member of the scientific advisory boards of Personalis and Genapsys.
- Choi YS, Zhang Y, Xu M, Yang Y, Ito M, Peng T, Cui Z, Nagy A, Hadjantonakis AK, Lang RA et al (2013) Distinct functions for Wnt/beta-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13:720–733CrossRefPubMedPubMedCentralGoogle Scholar
- Gejyo F, Chang JL, Burgi W, Schmid K, Offner GD, Troxler RF, Van Halbeek H, Dorland L, Gerwig GJ, Vliegenthart JF (1983) Characterization of the B-chain of human plasma alpha 2HS-glycoprotein. The complete amino acid sequence and primary structure of its heteroglycan. J Biol Chem 258:4966–4971PubMedGoogle Scholar
- Iliodromiti S, Vrachnis N, Samoli E, Iliodromiti Z, Pangalos C, Drakoulis N, Creatsas G, Botsis D (2012) Fetuin A concentration in the second trimester amniotic fluid of fetuses with trisomy 21 appears to be lower: phenotypic considerations. Mediators Inflamm 2012:138971CrossRefPubMedPubMedCentralGoogle Scholar
- Li S, Iakoucheva LM, Mooney SD, Radivojac P (2010) Loss of post-translational modification sites in disease. Pac Symp Biocomput 337–347Google Scholar
- Miller ML, Jensen LJ, Diella F, Jorgensen C, Tinti M, Li L, Hsiung M, Parker SA, Bordeaux J, Sicheritz-Ponten T et al (2008) Linear motif atlas for phosphorylation-dependent signaling. Sci Signal 1:ra2Google Scholar
- Szweras M, Liu D, Partridge EA, Pawling J, Sukhu B, Clokie C, Jahnen-Dechent W, Tenenbaum HC, Swallow CJ, Grynpas MD et al (2002) alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling. J Biol Chem 277:19991–19997CrossRefPubMedGoogle Scholar