期刊
NATURE GENETICS
卷 49, 期 2, 页码 238-248出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3743
关键词
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资金
- National Institutes of Health ((NIH)) [R00MH095867, R01HD081256, P01GM061354, T32HD007396, P50HD028138]
- MGH Robert and Laura Reynolds Research Scholar Award [R01HD043341]
- March of Dimes [FY15-255]
- Medical Research Council [MR/M02122X/1]
- German Research Foundation [SFB665]
- Berlin Institute of Health (BIH) [CRG1]
- Medical Research Council (MRC) Human Genetics Unit award [MC_PC_U127574433]
- University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund
- [K23HD073304-02]
- [1SI2ES025429-01]
- [P50DK096415]
- [R01AR062587]
- [U54-NS053672]
- MRC [MC_U127561093, MC_PC_U127561093, MC_PC_U127527199, MR/M02122X/1, MC_PC_U127574433, MC_U127527199] Funding Source: UKRI
- Fight for Sight [1590/91] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561093, MR/M02122X/1, MC_PC_U127527199, MC_U127527199, MC_PC_U127574433, MC_U127561093] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [16KT0112, 16H05159] Funding Source: KAKEN
Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
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