SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain

Lemmers, Richard J.L.F.; Stoep, Nienke van der; Vliet, Patrick J. van der; Moore, Steven A.; León, David San; Johnson, Katherine; Töpf, Ana; Straub, Volker; Evangelista, Teresinha; Mozaffar, Tahseen; Kimonis, Virginia; Shaw, Natalie D; Selvatici, Rita; Ferlini, Alessandra; Voermans, Nicol C.; Engelen, B.G.M. van; Sacconi, Sabrina; Tawil, Rabi; Lamers, Meindert H.; Maarel, Silvère M. van der

doi:10.1136/jmedgenet-2019-106168

Cited by 33 publications

(45 citation statements)

References 50 publications

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“…In contrast, SMCHD1 variants found in FSHD families include nonsense and insertion-deletion variants. As the SMCHD1 protein forms dimers, SMCHD1 variants that preserve the open reading frame most likely exert a dominant negative effect [14,15,22,35]. Another explanation for the milder effect of the Dnmt3b MommeD14 variant at the D4Z4 repeat array is that SMCHD1 might have a more potent role in epigenetic repression of the D4Z4 repeat array than DNMT3B.…”

Section: Discussionmentioning

confidence: 99%

Dnmt3b regulates DUX4 expression in a tissue-dependent manner in transgenic D4Z4 mice

Bouwman¹,

Hamer²,

Verveer³

et al. 2020

Skeletal Muscle

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Background Facioscapulohumeral muscular dystrophy (FSHD) is a skeletal muscle disorder that is caused by derepression of the transcription factor DUX4 in skeletal muscle cells. Apart from SMCHD1, DNMT3B was recently identified as a disease gene and disease modifier in FSHD. However, the exact role of DNMT3B at the D4Z4 repeat array remains unknown. Methods To determine the role of Dnmt3b on DUX4 repression, hemizygous mice with a FSHD-sized D4Z4 repeat array (D4Z4-2.5 mice) were cross-bred with mice carrying an in-frame exon skipping mutation in Dnmt3b (Dnmt3bMommeD14 mice). Additionally, siRNA knockdowns of Dnmt3b were performed in mouse embryonic stem cells (mESCs) derived from the D4Z4-2.5 mouse model. Results In mESCs derived from D4Z4-2.5 mice, Dnmt3b was enriched at the D4Z4 repeat array and DUX4 transcript levels were upregulated after a knockdown of Dnmt3b. In D4Z4-2.5/Dnmt3bMommeD14 mice, Dnmt3b protein levels were reduced; however, DUX4 RNA levels in skeletal muscles were not enhanced and no pathology was observed. Interestingly, D4Z4-2.5/Dnmt3bMommeD14 mice showed a loss of DNA methylation at the D4Z4 repeat array and significantly higher DUX4 transcript levels in secondary lymphoid organs. As these lymphoid organs seem to be more sensitive to epigenetic modifiers of the D4Z4 repeat array, different immune cell populations were quantified in the spleen and inguinal lymph nodes of D4Z4-2.5 mice crossed with Dnmt3bMommeD14 mice or Smchd1MommeD1 mice. Only in D4Z4-2.5/Smchd1MommeD1 mice the immune cell populations were disturbed. Conclusions Our data demonstrates that loss of Dnmt3b results in derepression of DUX4 in lymphoid tissues and mESCs but not in myogenic cells of D4Z4-2.5/Dnmt3bMommeD14 mice. In addition, the Smchd1MommeD1 variant seems to have a more potent role in DUX4 derepression. Our studies suggest that the immune system is particularly but differentially sensitive to D4Z4 chromatin modifiers which may provide a molecular basis for the yet underexplored immune involvement in FSHD.

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Section: Discussionmentioning

confidence: 99%

Dnmt3b regulates DUX4 expression in a tissue-dependent manner in transgenic D4Z4 mice

Bouwman¹,

Hamer²,

Verveer³

et al. 2020

Skeletal Muscle

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“…with Bosma arhinia microphthalmia syndrome (BAMS), an extremely rare syndrome whose triad is the absence of the nose, microphthalmia, and IHH [16][17][18] . In addition, SMCHD1 mutations are known to cause facioscapulohumeral muscular dystrophy type 2 (FSHD2), particularly when the mutations co-occurred with disease-susceptible alleles at the D4Z4 locus 19,20 .…”

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confidence: 99%

“…BAMS/FSHD2 patients with SMCHD1 mutations frequently exhibit DNA hypomethylation in the DUX4 promoter region at the D4Z4 locus, possibly reflecting impaired regulatory activity of the mutant SMCHD1 proteins 16,19 . Previous studies revealed that BAMS-causative SMCHD1 mutations consist solely of missense substitutions within or very close to the GHKL ATPase domain, while FSHD2-causative mutations include several missense, nonsense, and frameshift variants widely distributed in the 48 coding exons [16][17][18] . It has been proposed that gain-of-function and loss-of-function mutations in SMCHD1 result in BAMS and FSHD2, respectively, although four mutations have been associated with both conditions 16,18,21,22 .…”

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confidence: 99%

“…Previous studies revealed that BAMS-causative SMCHD1 mutations consist solely of missense substitutions within or very close to the GHKL ATPase domain, while FSHD2-causative mutations include several missense, nonsense, and frameshift variants widely distributed in the 48 coding exons [16][17][18] . It has been proposed that gain-of-function and loss-of-function mutations in SMCHD1 result in BAMS and FSHD2, respectively, although four mutations have been associated with both conditions 16,18,21,22 . More than 40 sporadic and familial cases with BAMS due to SMCHD1 mutations have been reported to date [16][17][18] .…”

mentioning

confidence: 99%

“…It has been proposed that gain-of-function and loss-of-function mutations in SMCHD1 result in BAMS and FSHD2, respectively, although four mutations have been associated with both conditions 16,18,21,22 . More than 40 sporadic and familial cases with BAMS due to SMCHD1 mutations have been reported to date [16][17][18] . Clinical analysis of the familial cases suggested variable expressivity of the BAMS triad 16 .…”

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Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency

Kinjo

Nagasaki

Muroya

et al. 2020

Sci Rep

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Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum. Hypogonadotropic hypogonadism (HH) is a multifactorial disorder that occurs either as an isolated hormonal abnormality (isolated HH, IHH) or in combination with other pituitary hormone deficiencies (combined pituitary hormone deficiency, CPHD) 1,2. HH is frequently accompanied by craniofacial and neurological abnormalities, such as microphthalmia, anosmia, and septum pellucidum/corpus callosum hypoplasia 2-6. The current understanding is that IHH and CPHD belong to a disease spectrum, which includes septo-optic dysplasia (SOD) and holoprosencephaly at the most severe end and IHH at the mildest end 1,7. This disease spectrum results from defective organogenesis from the cranial placodes 1,8. To date, more than 40 genes have been implicated in this disease spectrum 1,9. However, mutations in these genes account for only about 50% of IHH cases and less than 20% of CPHD cases, indicating that other causative genes remain to be identified 1,9. SMCHD1 encodes an epigenetic regulator that controls DNA methylation of multiple genomic loci 10-12. Previous studies have shown that SMCHD1 is involved in the regulation of several monoallelically expressed genes 11,13 , and is particularly enriched in the nuclear territory of the inactive X chromosome (Xi) 14, 15. Yet, the precise function of this protein remains to be clarified. Recently, heterozygous SMCHD1 mutations were identified in patients

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Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report

Atencia Goñi,

Orera Clemente,

Del Valle Diéguez

et al. 2024

Endocrinología, Diabetes y Nutrición (English ed.)

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SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain

Cited by 33 publications

References 50 publications

Dnmt3b regulates DUX4 expression in a tissue-dependent manner in transgenic D4Z4 mice

Dnmt3b regulates DUX4 expression in a tissue-dependent manner in transgenic D4Z4 mice

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency

Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report

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