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SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

ABSTRACT: 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.

SUBMITTER: Shaw ND

PROVIDER: S-EPMC5473428 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Shaw Natalie D ND Brand Harrison H Kupchinsky Zachary A ZA Bengani Hemant H Plummer Lacey L Jones Takako I TI Erdin Serkan S Williamson Kathleen A KA Rainger Joe J Stortchevoi Alexei A Samocha Kaitlin K Currall Benjamin B BB Dunican Donncha S DS Collins Ryan L RL Willer Jason R JR Lek Angela A Lek Monkol M Nassan Malik M Pereira Shahrin S Kammin Tammy T Lucente Diane D Silva Alexandra A Seabra Catarina M CM Chiang Colby C An Yu Y Ansari Morad M Rainger Jacqueline K JK Joss Shelagh S Smith Jill Clayton JC Lippincott Margaret F MF Singh Sylvia S SS Patel Nirav N Jing Jenny W JW Law Jennifer R JR Ferraro Nalton N Verloes Alain A Rauch Anita A Steindl Katharina K Zweier Markus M Scheer Ianina I Sato Daisuke D Okamoto Nobuhiko N Jacobsen Christina C Tryggestad Jeanie J Chernausek Steven S Schimmenti Lisa A LA Brasseur Benjamin B Cesaretti Claudia C García-Ortiz Jose E JE Buitrago Tatiana Pineda TP Silva Orlando Perez OP Hoffman Jodi D JD Mühlbauer Wolfgang W Ruprecht Klaus W KW Loeys Bart L BL Shino Masato M Kaindl Angela M AM Cho Chie-Hee CH Morton Cynthia C CC Meehan Richard R RR van Heyningen Veronica V Liao Eric C EC Balasubramanian Ravikumar R Hall Janet E JE Seminara Stephanie B SB Macarthur Daniel D Moore Steven A SA Yoshiura Koh-Ichiro KI Gusella James F JF Marsh Joseph A JA Graham John M JM Lin Angela E AE Katsanis Nicholas N Jones Peter L PL Crowley William F WF Davis Erica E EE FitzPatrick David R DR Talkowski Michael E ME

Nature genetics 20170109 2

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 hypomet ...[more]

PMID: 28067909

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Project description:MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Dataset Information

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Publications

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Similar Datasets

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