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

Natalie D Shaw; Harrison Brand; Zachary A Kupchinsky; Hemant Bengani; Lacey Plummer; Takako I Jones; Serkan Erdin; Kathleen A Williamson; Joe Rainger; Alexei Stortchevoi; Kaitlin Samocha; Benjamin B Currall; Donncha S Dunican; Ryan L Collins; Jason R Willer; Angela Lek; Monkol Lek; Malik Nassan; Shahrin Pereira; Tammy Kammin; Diane Lucente; Alexandra Silva; Catarina M Seabra; Colby Chiang; Yu An; Morad Ansari; Jacqueline K Rainger; Shelagh Joss; Jill Clayton Smith; Margaret F Lippincott; Sylvia S Singh; Nirav Patel; Jenny W Jing; Jennifer R Law; Nalton Ferraro; Alain Verloes; Anita Rauch; Katharina Steindl; Markus Zweier; Ianina Scheer; Daisuke Sato; Nobuhiko Okamoto; Christina Jacobsen; Jeanie Tryggestad; Steven Chernausek; Lisa A Schimmenti; Benjamin Brasseur; Claudia Cesaretti; Jose E García-Ortiz; Tatiana Pineda Buitrago; Orlando Perez Silva; Jodi D Hoffman; Wolfgang Mühlbauer; Klaus W Ruprecht; Bart L Loeys; Masato Shino; Angela M Kaindl; Chie-Hee Cho; Cynthia C Morton; Richard R Meehan; Veronica van Heyningen; Eric C Liao; Ravikumar Balasubramanian; Janet E Hall; Stephanie B Seminara; Daniel Macarthur; Steven A Moore; Koh-ichiro Yoshiura; James F Gusella; Joseph A Marsh; John M Graham Jr; Angela E Lin; Nicholas Katsanis; Peter L Jones; William F Crowley Jr; Erica E Davis; David R FitzPatrick; Michael E Talkowski

doi:10.1038/ng.3743

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

Natalie D Shaw, Harrison Brand, Zachary A Kupchinsky, Hemant Bengani, Lacey Plummer, Takako I Jones, Serkan Erdin, Kathleen A Williamson, Joe Rainger, Alexei Stortchevoi, Kaitlin Samocha, Benjamin B Currall, Donncha S Dunican, Ryan L Collins, Jason R Willer, Angela Lek, Monkol Lek, Malik Nassan, Shahrin Pereira, Tammy KamminDiane Lucente, Alexandra Silva, Catarina M Seabra, Colby Chiang, Yu An, Morad Ansari, Jacqueline K Rainger, Shelagh Joss, Jill Clayton Smith, Margaret F Lippincott, Sylvia S Singh, Nirav Patel, Jenny W Jing, Jennifer R Law, Nalton Ferraro, Alain Verloes, Anita Rauch, Katharina Steindl, Markus Zweier, Ianina Scheer, Daisuke Sato, Nobuhiko Okamoto, Christina Jacobsen, Jeanie Tryggestad, Steven Chernausek, Lisa A Schimmenti, Benjamin Brasseur, Claudia Cesaretti, Jose E García-Ortiz, Tatiana Pineda Buitrago, Orlando Perez Silva, Jodi D Hoffman, Wolfgang Mühlbauer, Klaus W Ruprecht, Bart L Loeys, Masato Shino, Angela M Kaindl, Chie-Hee Cho, Cynthia C Morton, Richard R Meehan, Veronica van Heyningen, Eric C Liao, Ravikumar Balasubramanian, Janet E Hall, Stephanie B Seminara, Daniel Macarthur, Steven A Moore, Koh-ichiro Yoshiura, James F Gusella, Joseph A Marsh, John M Graham Jr, Angela E Lin, Nicholas Katsanis, Peter L Jones, William F Crowley Jr, Erica E Davis, David R FitzPatrick, Michael E Talkowski

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	238-248
Number of pages	11
Journal	Nature Genetics
Volume	49
Issue number	2
Early online date	9 Jan 2017
DOIs	https://doi.org/10.1038/ng.3743
Publication status	Published - Feb 2017

Access to Document

10.1038/ng.3743

NG_A43728R_Talkowski_MS_090416Accepted author manuscript, 528 KB

HGU Core Award Apr 12 - MAr 18
Hastie, N. (Principal Investigator), Adams, I. (Co-investigator), Baldock, R. (Co-investigator), Bickmore, W. (Co-investigator), Caceres, J. (Co-investigator), Dorin, J. (Co-investigator), FitzPatrick, D. (Co-investigator), Haley, C. (Co-investigator), Hill, B. (Co-investigator), Jackson, I. (Co-investigator), Jackson, A. (Co-investigator), Kudla, G. (Co-investigator), Meehan, R. (Co-investigator) & Patton, E. (Co-investigator)
MRC
1/04/12 → 31/03/18
Project: Research

Richard Meehan
- MRC Human Genetics Unit
Person: Academic: Research Active
Joe Rainger
- joe.raingerroslin.ed.acuk
- Royal (Dick) School of Veterinary Studies - Senior Research Fellow
Person: Academic: Research Active

Cite this

Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., Dunican, D. S., Collins, R. L., Willer, J. R., Lek, A., Lek, M., Nassan, M., Pereira, S., ... Talkowski, M. E. (2017). SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nature Genetics, 49(2), 238-248. https://doi.org/10.1038/ng.3743

@article{820a5de31bc54a4fbb2542d70de0d031,

title = "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.",

author = "Shaw, {Natalie D} and Harrison Brand and Kupchinsky, {Zachary A} and Hemant Bengani and Lacey Plummer and Jones, {Takako I} and Serkan Erdin and Williamson, {Kathleen A} and Joe Rainger and Alexei Stortchevoi and Kaitlin Samocha and Currall, {Benjamin B} and Dunican, {Donncha S} and Collins, {Ryan L} and Willer, {Jason R} and Angela Lek and Monkol Lek and Malik Nassan and Shahrin Pereira and Tammy Kammin and Diane Lucente and Alexandra Silva and Seabra, {Catarina M} and Colby Chiang and Yu An and Morad Ansari and Rainger, {Jacqueline K} and Shelagh Joss and Smith, {Jill Clayton} and Lippincott, {Margaret F} and Singh, {Sylvia S} and Nirav Patel and Jing, {Jenny W} and Law, {Jennifer R} and Nalton Ferraro and Alain Verloes and Anita Rauch and Katharina Steindl and Markus Zweier and Ianina Scheer and Daisuke Sato and Nobuhiko Okamoto and Christina Jacobsen and Jeanie Tryggestad and Steven Chernausek and Schimmenti, {Lisa A} and Benjamin Brasseur and Claudia Cesaretti and Garc{\'i}a-Ortiz, {Jose E} and Buitrago, {Tatiana Pineda} and Silva, {Orlando Perez} and Hoffman, {Jodi D} and Wolfgang M{\"u}hlbauer and Ruprecht, {Klaus W} and Loeys, {Bart L} and Masato Shino and Kaindl, {Angela M} and Chie-Hee Cho and Morton, {Cynthia C} and Meehan, {Richard R} and {van Heyningen}, Veronica and Liao, {Eric C} and Ravikumar Balasubramanian and Hall, {Janet E} and Seminara, {Stephanie B} and Daniel Macarthur and Moore, {Steven A} and Koh-ichiro Yoshiura and Gusella, {James F} and Marsh, {Joseph A} and {Graham Jr}, {John M} and Lin, {Angela E} and Nicholas Katsanis and Jones, {Peter L} and {Crowley Jr}, {William F} and Davis, {Erica E} and FitzPatrick, {David R} and Talkowski, {Michael E}",

year = "2017",

month = feb,

doi = "10.1038/ng.3743",

language = "English",

volume = "49",

pages = "238--248",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

Shaw, ND, Brand, H, Kupchinsky, ZA, Bengani, H, Plummer, L, Jones, TI, Erdin, S, Williamson, KA , Rainger, J, Stortchevoi, A, Samocha, K, Currall, BB, Dunican, DS, Collins, RL, Willer, JR, Lek, A, Lek, M, Nassan, M, Pereira, S, Kammin, T, Lucente, D, Silva, A, Seabra, CM, Chiang, C, An, Y, Ansari, M, Rainger, JK, Joss, S, Smith, JC, Lippincott, MF, Singh, SS, Patel, N, Jing, JW, Law, JR, Ferraro, N, Verloes, A, Rauch, A, Steindl, K, Zweier, M, Scheer, I, Sato, D, Okamoto, N, Jacobsen, C, Tryggestad, J, Chernausek, S, Schimmenti, LA, Brasseur, B, Cesaretti, C, García-Ortiz, JE, Buitrago, TP, Silva, OP, Hoffman, JD, Mühlbauer, W, Ruprecht, KW, Loeys, BL, Shino, M, Kaindl, AM, Cho, C-H, Morton, CC, Meehan, RR, van Heyningen, V, Liao, EC, Balasubramanian, R, Hall, JE, Seminara, SB, Macarthur, D, Moore, SA, Yoshiura, K, Gusella, JF, Marsh, JA, Graham Jr, JM, Lin, AE, Katsanis, N, Jones, PL, Crowley Jr, WF, Davis, EE, FitzPatrick, DR & Talkowski, ME 2017, 'SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome', Nature Genetics, vol. 49, no. 2, pp. 238-248. https://doi.org/10.1038/ng.3743

TY - JOUR

T1 - SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

AU - Shaw, Natalie D

AU - Brand, Harrison

AU - Kupchinsky, Zachary A

AU - Bengani, Hemant

AU - Plummer, Lacey

AU - Jones, Takako I

AU - Erdin, Serkan

AU - Williamson, Kathleen A

AU - Rainger, Joe

AU - Stortchevoi, Alexei

AU - Samocha, Kaitlin

AU - Currall, Benjamin B

AU - Dunican, Donncha S

AU - Collins, Ryan L

AU - Willer, Jason R

AU - Lek, Angela

AU - Lek, Monkol

AU - Nassan, Malik

AU - Pereira, Shahrin

AU - Kammin, Tammy

AU - Lucente, Diane

AU - Silva, Alexandra

AU - Seabra, Catarina M

AU - Chiang, Colby

AU - An, Yu

AU - Ansari, Morad

AU - Rainger, Jacqueline K

AU - Joss, Shelagh

AU - Smith, Jill Clayton

AU - Lippincott, Margaret F

AU - Singh, Sylvia S

AU - Patel, Nirav

AU - Jing, Jenny W

AU - Law, Jennifer R

AU - Ferraro, Nalton

AU - Verloes, Alain

AU - Rauch, Anita

AU - Steindl, Katharina

AU - Zweier, Markus

AU - Scheer, Ianina

AU - Sato, Daisuke

AU - Okamoto, Nobuhiko

AU - Jacobsen, Christina

AU - Tryggestad, Jeanie

AU - Chernausek, Steven

AU - Schimmenti, Lisa A

AU - Brasseur, Benjamin

AU - Cesaretti, Claudia

AU - García-Ortiz, Jose E

AU - Buitrago, Tatiana Pineda

AU - Silva, Orlando Perez

AU - Hoffman, Jodi D

AU - Mühlbauer, Wolfgang

AU - Ruprecht, Klaus W

AU - Loeys, Bart L

AU - Shino, Masato

AU - Kaindl, Angela M

AU - Cho, Chie-Hee

AU - Morton, Cynthia C

AU - Meehan, Richard R

AU - van Heyningen, Veronica

AU - Liao, Eric C

AU - Balasubramanian, Ravikumar

AU - Hall, Janet E

AU - Seminara, Stephanie B

AU - Macarthur, Daniel

AU - Moore, Steven A

AU - Yoshiura, Koh-ichiro

AU - Gusella, James F

AU - Marsh, Joseph A

AU - Graham Jr, John M

AU - Lin, Angela E

AU - Katsanis, Nicholas

AU - Jones, Peter L

AU - Crowley Jr, William F

AU - Davis, Erica E

AU - FitzPatrick, David R

AU - Talkowski, Michael E

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3743

DO - 10.1038/ng.3743

M3 - Article

C2 - 28067909

SN - 1061-4036

VL - 49

SP - 238

EP - 248

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

Abstract

Access to Document

Fingerprint

Projects

HGU Core Award Apr 12 - MAr 18

Profiles

Richard Meehan

Joe Rainger

Cite this