6mw7

Structural highlights

Disease

SMHD1_HUMAN Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome;Facioscapulohumeral dystrophy. The disease is caused by mutations affecting the gene represented in this entry. SMCHD1 mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression (PubMed:23143600). Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death (PubMed:23143600). FSHD2 and FSHD1 share a common pathophysiological pathway in which the FSHD2 gene SMCHD1 can act as a modifier for disease severity in families affected by FSHD1 (PubMed:24075187, PubMed:25370034).^{[1] [2] [3]} The disease is caused by mutations affecting the gene represented in this entry.

Function

SMHD1_HUMAN Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture (By similarity). Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments (By similarity). Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin (PubMed:23542155). Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X (By similarity). Required to facilitate Xist RNA spreading (By similarity). Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus (PubMed:23143600). Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation (PubMed:29748383). Also plays a role in DNA repair: localizes to sites of DNA double-strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks (PubMed:25294876, PubMed:24790221). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (PubMed:25294876).[UniProtKB:Q6P5D8]^{[4] [5] [6] [7] [8]}

References

1. ↑ Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11. PMID:23143600 doi:http://dx.doi.org/10.1038/ng.2454
2. ↑ Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, Casarin A, Pegoraro E, Tawil R, Bakker E, Tapscott SJ, Desnuelle C, van der Maarel SM. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. 2013 Oct 3;93(4):744-51. doi: 10.1016/j.ajhg.2013.08.004. Epub, 2013 Sep 26. PMID:24075187 doi:http://dx.doi.org/10.1016/j.ajhg.2013.08.004
3. ↑ Larsen M, Rost S, El Hajj N, Ferbert A, Deschauer M, Walter MC, Schoser B, Tacik P, Kress W, Muller CR. Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet. 2015 Jun;23(6):808-16. doi: 10.1038/ejhg.2014.191. Epub 2014 Nov, 5. PMID:25370034 doi:http://dx.doi.org/10.1038/ejhg.2014.191
4. ↑ Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11. PMID:23143600 doi:http://dx.doi.org/10.1038/ng.2454
5. ↑ Nozawa RS, Nagao K, Igami KT, Shibata S, Shirai N, Nozaki N, Sado T, Kimura H, Obuse C. Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway. Nat Struct Mol Biol. 2013 May;20(5):566-73. doi: 10.1038/nsmb.2532. Epub 2013 Mar, 31. PMID:23542155 doi:http://dx.doi.org/10.1038/nsmb.2532
6. ↑ Coker H, Brockdorff N. SMCHD1 accumulates at DNA damage sites and facilitates the repair of DNA double-strand breaks. J Cell Sci. 2014 May 1;127(Pt 9):1869-74. doi: 10.1242/jcs.140020. PMID:24790221 doi:http://dx.doi.org/10.1242/jcs.140020
7. ↑ Tang M, Li Y, Zhang X, Deng T, Zhou Z, Ma W, Songyang Z. Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) promotes non-homologous end joining and inhibits homologous recombination repair upon DNA damage. J Biol Chem. 2014 Dec 5;289(49):34024-32. doi: 10.1074/jbc.M114.601179. Epub 2014, Oct 7. PMID:25294876 doi:http://dx.doi.org/10.1074/jbc.M114.601179
8. ↑ Gurzau AD, Chen K, Xue S, Dai W, Lucet IS, Ly TTN, Reversade B, Blewitt ME, Murphy JM. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. J Biol Chem. 2018 Jun 22;293(25):9841-9853. doi: 10.1074/jbc.RA118.003104. Epub, 2018 May 10. PMID:29748383 doi:http://dx.doi.org/10.1074/jbc.RA118.003104
9. ↑ Pedersen LC, Inoue K, Kim S, Perera L, Shaw ND. A ubiquitin-like domain is required for stabilizing the N-terminal ATPase module of human SMCHD1. Commun Biol. 2019 Jul 10;2:255. doi: 10.1038/s42003-019-0499-y. eCollection 2019. PMID:31312724 doi:http://dx.doi.org/10.1038/s42003-019-0499-y