Article | Published:

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

Nature Genetics volume 49, pages 238248 (2017) | Download Citation

  • A Corrigendum to this article was published on 26 May 2017

This article has been updated

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.

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Change history

  • 20 March 2017

    In the version of this article initially published, the legend to Figure 4c stated that only one proband without SMCHD1 mutation was tested for D4Z4 methylation pattern. However, three probands and one affected family member without SMCHD1 mutation were tested, as shown in the figure. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank all participants, family members and clinical staff for their generous contributions of time and materials to this research. We thank T. Gillis, J. Ruliera, C. Hanscom, C. Antolik and M. Anderson for technical assistance. This project was funded by grants from the National Institutes of Health ((NIH) R00MH095867 and R01HD081256 to M.E.T.; P01GM061354 to M.E.T., J.F.G., C.C.M. and E.C.L.; T32HD007396 to H. Brand; P50HD028138 to W.F.C., S.B.S., M.E.T., N.K. and E.E.D.; R01HD043341 and MGH Robert and Laura Reynolds Research Scholar Award to S.B.S.; K23HD073304-02 and 1SI2ES025429-01 to N.D.S.; P50DK096415 to N.K. and R01AR062587 to P.L.J.); the March of Dimes (FY15-255 to M.E.T.); the Medical Research Council (MR/M02122X/1 to J.A.M.); the German Research Foundation (SFB665 to A.M.K.) and the Berlin Institute of Health (BIH-CRG1 to A.M.K.). D.R.F., R.R.M. (MC_PC_U127574433), D.S.D., H. Bengani, K.A.W., J.R., J.K.R. and J.A.M. are funded by program grants from the Medical Research Council (MRC) Human Genetics Unit award to the University of Edinburgh. M.A. is funded by the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund. S.A.M. is supported by U54-NS053672, which funds the Iowa, Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. N.K. is supported as a Distinguished Jean and George Brumley Professor at Duke University, and M.E.T. is supported as the Desmond and Ann Heathwood MGH Research Scholar.

Author information

Author notes

    • Natalie D Shaw
    •  & Harrison Brand

    These authors contributed equally to this work.

Affiliations

  1. Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Natalie D Shaw
    • , Harrison Brand
    • , Lacey Plummer
    • , Margaret F Lippincott
    • , Sylvia S Singh
    • , Nirav Patel
    • , Jenny W Jing
    • , Ravikumar Balasubramanian
    • , Janet E Hall
    • , Stephanie B Seminara
    •  & William F Crowley Jr
  2. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

    • Natalie D Shaw
    •  & Janet E Hall
  3. Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Harrison Brand
    • , Serkan Erdin
    • , Alexei Stortchevoi
    • , Benjamin B Currall
    • , Ryan L Collins
    • , Diane Lucente
    • , Alexandra Silva
    • , Catarina M Seabra
    • , Colby Chiang
    • , Yu An
    • , James F Gusella
    •  & Michael E Talkowski
  4. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Harrison Brand
    • , James F Gusella
    •  & Michael E Talkowski
  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Harrison Brand
    • , Serkan Erdin
    • , Kaitlin Samocha
    • , Monkol Lek
    • , Cynthia C Morton
    • , Daniel Macarthur
    • , James F Gusella
    •  & Michael E Talkowski
  6. Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.

    • Zachary A Kupchinsky
    • , Jason R Willer
    • , Nicholas Katsanis
    •  & Erica E Davis
  7. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.

    • Hemant Bengani
    • , Kathleen A Williamson
    • , Joe Rainger
    • , Donncha S Dunican
    • , Morad Ansari
    • , Jacqueline K Rainger
    • , Richard R Meehan
    • , Veronica van Heyningen
    • , Joseph A Marsh
    •  & David R FitzPatrick
  8. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Takako I Jones
    •  & Peter L Jones
  9. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Kaitlin Samocha
    • , Monkol Lek
    •  & Daniel Macarthur
  10. Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Ryan L Collins
  11. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Angela Lek
    •  & James F Gusella
  12. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.

    • Malik Nassan
  13. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Shahrin Pereira
    • , Tammy Kammin
    •  & Cynthia C Morton
  14. GABBA Program, University of Porto, Porto, Portugal.

    • Catarina M Seabra
  15. West of Scotland Genetics Service, South Glasgow University Hospitals, Glasgow, UK.

    • Shelagh Joss
  16. Faculty of Medical and Human Sciences, Institute of Human Development, Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.

    • Jill Clayton Smith
  17. Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Jennifer R Law
  18. Department of Oral and Maxillofacial Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Nalton Ferraro
  19. Department of Genetics, Robert Debré Hospital, Paris, France.

    • Alain Verloes
  20. Institute of Medical Genetics and Radiz–Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland.

    • Anita Rauch
    • , Katharina Steindl
    •  & Markus Zweier
  21. Department of Diagnostic Imaging, Children's Hospital, Zurich, Switzerland.

    • Ianina Scheer
  22. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

    • Daisuke Sato
  23. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.

    • Nobuhiko Okamoto
  24. Division of Endocrinology and Genetics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Christina Jacobsen
  25. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Jeanie Tryggestad
    •  & Steven Chernausek
  26. Departments of Otorhinolaryngology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.

    • Lisa A Schimmenti
  27. DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.

    • Benjamin Brasseur
  28. Medical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.

    • Claudia Cesaretti
  29. División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico.

    • Jose E García-Ortiz
  30. Fundación Hospital Infantil Universitario de San José, Bogotá, Colombia.

    • Tatiana Pineda Buitrago
  31. Academia Nacional de Medicina de Colombia, Bogotá, Colombia.

    • Orlando Perez Silva
  32. Divisions of Genetics and Maternal Fetal Medicine, Tufts Medical Center, Boston, Massachusetts, USA.

    • Jodi D Hoffman
  33. Department of Plastic and Aesthetic Surgery, ATOS Klinik, Munich, Germany.

    • Wolfgang Mühlbauer
  34. Department of Ophthalmology, University Hospital of the Saarland, Homburg, Germany.

    • Klaus W Ruprecht
  35. Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

    • Bart L Loeys
  36. Department of Otolaryngology and Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.

    • Masato Shino
  37. Biology and Neurobiology, Charité–University Medicine Berlin and Berlin Institute of Health, Berlin, Germany.

    • Angela M Kaindl
  38. Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University Hospital of Bern, Bern, Switzerland.

    • Chie-Hee Cho
  39. Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Eric C Liao
  40. Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Eric C Liao
  41. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.

    • Eric C Liao
  42. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Daniel Macarthur
    •  & Michael E Talkowski
  43. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

    • Steven A Moore
  44. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

    • Koh-ichiro Yoshiura
  45. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA.

    • John M Graham Jr
  46. Medical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, USA.

    • Angela E Lin

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Contributions

M.E.T., D.R.F., E.E.D., N.K., P.J., N.D.S. and H. Brand designed the study. N.D.S., L.P., K.A.W., M.N., S.P., T.K., D.L., A. Silva, S.J., J.C.S., M.F.L., S.S.S., N.P., J.R.L., N.F., A.V., A.R., K. Steindl, I.S., D.S., N.O., C.J., J.T., S.C., L.A.S., B.B., C. Cesaretti, J.E.G.-O., T.P.B., O.P.S., J.D.H., W.M., K.W.R., B.L.L., M.S., A.M.K., C.-H.C., C.C.M., V.v.H., R.B., J.E.H., S.B.S., K.Y., J.M.G., A.E.L., W.F.C. and D.R.F. recruited patients and collected clinical information and samples. Z.A.K., H. Bengani, L.P., S.E., T.I.J., J.R.W., J.R., A. Stortchevoi, C.M.S., Y.A., B.B.C., M.A., R.R.M., J.K.R., M.Z., J.W.J., E.C.L., S.A.M., N.K., P.L.J., E.E.D., D.R.F. and D.S.D. performed molecular genetics and animal modeling studies. H. Brand, K. Samocha, R.L.C., C. Chiang, A.L., M.L., J.F.G., D.G.M. and M.E.T. performed genomic analyses. J.A.M. performed protein modeling. N.D.S., H. Brand, N.K., J.F.G., P.L.J., E.E.D., D.R.F. and M.E.T. wrote the manuscript, which was revised and approved by all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Erica E Davis or David R FitzPatrick or Michael E Talkowski.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11

Excel files

  1. 1.

    Supplementary Table 1

    Arhina cohort-wide phenotype information.

  2. 2.

    Supplementary Table 2

    Individual level phenotype information.

  3. 3.

    Supplementary Table 3

    Ethnic specific analysis of SMCHD1 mutation frequency.

  4. 4.

    Supplementary Table 4

    DNA methylation analysis of D4Z4 repeats in arhinia cases and familial controls.

  5. 5.

    Supplementary Table 5

    Representative zebrafish morphometric data.

  6. 6.

    Supplementary Table 6

    Mouse CRISPR of SMCHD1 missense mutations.

  7. 7.

    Supplementary Table 7

    Allele-specific expression of SMCHD1 in subjects with a mutation.

  8. 8.

    Supplementary Table 8

    Differential expression analysis between arhinia cases and familial controls.

  9. 9.

    Supplementary Table 9

    Enrichment of nominal human genes (P < 0.05) against mouse Smchd1 targets and differentially expressed genes in Smchd1-null mouse.

  10. 10.

    Supplementary Table 10

    Overlapping genes with significant dysregulation in the same direction in mouse and human.

  11. 11.

    Supplementary Table 11

    Primers used in study.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3743

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