De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Christopher T. Gordon; Shifeng Xue; Gökhan Yigit; Hicham Filali; Kelan Chen; Nadine Rosin; Koh Ichiro Yoshiura; Myriam Oufadem; Tamara J. Beck; Ruth McGowan; Alex C. Magee; Janine Altmüller; Camille Dion; Holger Thiele; Alexandra D. Gurzau; Peter Nürnberg; Dieter Meschede; Wolfgang Mühlbauer; Nobuhiko Okamoto; Vinod Varghese; Rachel Irving; Sabine Sigaudy; Denise Williams; S. Faisal Ahmed; Carine Bonnard; Mung Kei Kong; Ilham Ratbi; Nawfal Fejjal; Meriem Fikri; Siham Chafai Elalaoui; Hallvard Reigstad; Christine Bole-Feysot; Patrick Nitschké; Nicola Ragge; Nicolas Lévy; Gökhan Tunçbilek; Audrey S.M. Teo; Michael L. Cunningham; Abdelaziz Sefiani; Hülya Kayserili; James M. Murphy; Chalermpong Chatdokmaiprai; Axel M. Hillmer; Duangrurdee Wattanasirichaigoon; Stanislas Lyonnet; Frédérique Magdinier; Asif Javed; Marnie E. Blewitt; Jeanne Amiel; Bernd Wollnik; Bruno Reversade

doi:10.1038/ng.3765

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Christopher T. Gordon, Shifeng Xue, Gökhan Yigit, Hicham Filali, Kelan Chen, Nadine Rosin, Koh Ichiro Yoshiura, Myriam Oufadem, Tamara J. Beck, Ruth McGowan, Alex C. Magee, Janine Altmüller, Camille Dion, Holger Thiele, Alexandra D. Gurzau, Peter Nürnberg, Dieter Meschede, Wolfgang Mühlbauer, Nobuhiko Okamoto, Vinod VargheseRachel Irving, Sabine Sigaudy, Denise Williams, S. Faisal Ahmed, Carine Bonnard, Mung Kei Kong, Ilham Ratbi, Nawfal Fejjal, Meriem Fikri, Siham Chafai Elalaoui, Hallvard Reigstad, Christine Bole-Feysot, Patrick Nitschké, Nicola Ragge, Nicolas Lévy, Gökhan Tunçbilek, Audrey S.M. Teo, Michael L. Cunningham, Abdelaziz Sefiani, Hülya Kayserili, James M. Murphy, Chalermpong Chatdokmaiprai, Axel M. Hillmer, Duangrurdee Wattanasirichaigoon, Stanislas Lyonnet, Frédérique Magdinier, Asif Javed, Marnie E. Blewitt, Jeanne Amiel, Bernd Wollnik, Bruno Reversade

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Abstract

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Original language	English (US)
Pages (from-to)	249-255
Number of pages	7
Journal	Nature Genetics
Volume	49
Issue number	2
DOIs	https://doi.org/10.1038/ng.3765
State	Published - Jan 31 2017
Externally published	Yes

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Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K. I., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmüller, J., Dion, C., Thiele, H., Gurzau, A. D., Nürnberg, P., Meschede, D., Mühlbauer, W., Okamoto, N., ... Reversade, B. (2017). De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nature Genetics, 49(2), 249-255. https://doi.org/10.1038/ng.3765

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title = "De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development",

abstract = "Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.",

author = "Gordon, {Christopher T.} and Shifeng Xue and G{\"o}khan Yigit and Hicham Filali and Kelan Chen and Nadine Rosin and Yoshiura, {Koh Ichiro} and Myriam Oufadem and Beck, {Tamara J.} and Ruth McGowan and Magee, {Alex C.} and Janine Altm{\"u}ller and Camille Dion and Holger Thiele and Gurzau, {Alexandra D.} and Peter N{\"u}rnberg and Dieter Meschede and Wolfgang M{\"u}hlbauer and Nobuhiko Okamoto and Vinod Varghese and Rachel Irving and Sabine Sigaudy and Denise Williams and Ahmed, {S. Faisal} and Carine Bonnard and Kong, {Mung Kei} and Ilham Ratbi and Nawfal Fejjal and Meriem Fikri and Elalaoui, {Siham Chafai} and Hallvard Reigstad and Christine Bole-Feysot and Patrick Nitschk{\'e} and Nicola Ragge and Nicolas L{\'e}vy and G{\"o}khan Tun{\c c}bilek and Teo, {Audrey S.M.} and Cunningham, {Michael L.} and Abdelaziz Sefiani and H{\"u}lya Kayserili and Murphy, {James M.} and Chalermpong Chatdokmaiprai and Hillmer, {Axel M.} and Duangrurdee Wattanasirichaigoon and Stanislas Lyonnet and Fr{\'e}d{\'e}rique Magdinier and Asif Javed and Blewitt, {Marnie E.} and Jeanne Amiel and Bernd Wollnik and Bruno Reversade",

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doi = "10.1038/ng.3765",

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Gordon, CT, Xue, S, Yigit, G, Filali, H, Chen, K, Rosin, N, Yoshiura, KI, Oufadem, M, Beck, TJ, McGowan, R, Magee, AC, Altmüller, J, Dion, C, Thiele, H, Gurzau, AD, Nürnberg, P, Meschede, D, Mühlbauer, W, Okamoto, N, Varghese, V, Irving, R, Sigaudy, S, Williams, D, Ahmed, SF, Bonnard, C, Kong, MK, Ratbi, I, Fejjal, N, Fikri, M, Elalaoui, SC, Reigstad, H, Bole-Feysot, C, Nitschké, P, Ragge, N, Lévy, N, Tunçbilek, G, Teo, ASM, Cunningham, ML, Sefiani, A, Kayserili, H, Murphy, JM, Chatdokmaiprai, C, Hillmer, AM, Wattanasirichaigoon, D, Lyonnet, S, Magdinier, F, Javed, A, Blewitt, ME, Amiel, J, Wollnik, B & Reversade, B 2017, 'De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development', Nature Genetics, vol. 49, no. 2, pp. 249-255. https://doi.org/10.1038/ng.3765

TY - JOUR

T1 - De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

AU - Gordon, Christopher T.

AU - Xue, Shifeng

AU - Yigit, Gökhan

AU - Filali, Hicham

AU - Chen, Kelan

AU - Rosin, Nadine

AU - Yoshiura, Koh Ichiro

AU - Oufadem, Myriam

AU - Beck, Tamara J.

AU - McGowan, Ruth

AU - Magee, Alex C.

AU - Altmüller, Janine

AU - Dion, Camille

AU - Thiele, Holger

AU - Gurzau, Alexandra D.

AU - Nürnberg, Peter

AU - Meschede, Dieter

AU - Mühlbauer, Wolfgang

AU - Okamoto, Nobuhiko

AU - Varghese, Vinod

AU - Irving, Rachel

AU - Sigaudy, Sabine

AU - Williams, Denise

AU - Ahmed, S. Faisal

AU - Bonnard, Carine

AU - Kong, Mung Kei

AU - Ratbi, Ilham

AU - Fejjal, Nawfal

AU - Fikri, Meriem

AU - Elalaoui, Siham Chafai

AU - Reigstad, Hallvard

AU - Bole-Feysot, Christine

AU - Nitschké, Patrick

AU - Ragge, Nicola

AU - Lévy, Nicolas

AU - Tunçbilek, Gökhan

AU - Teo, Audrey S.M.

AU - Cunningham, Michael L.

AU - Sefiani, Abdelaziz

AU - Kayserili, Hülya

AU - Murphy, James M.

AU - Chatdokmaiprai, Chalermpong

AU - Hillmer, Axel M.

AU - Wattanasirichaigoon, Duangrurdee

AU - Lyonnet, Stanislas

AU - Magdinier, Frédérique

AU - Javed, Asif

AU - Blewitt, Marnie E.

AU - Amiel, Jeanne

AU - Wollnik, Bernd

AU - Reversade, Bruno

N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

AB - Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

UR - http://www.nature.com/articles/ng.3765

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U2 - 10.1038/ng.3765

DO - 10.1038/ng.3765

M3 - Article

SN - 1061-4036

VL - 49

SP - 249

EP - 255

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

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