The SMAD-binding domain of SKI

A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

Dorien Schepers, Alexander J. Doyle, Gretchen Oswald, Elizabeth Sparks, Loretha Myers, Patrick J. Willems, Sahar Mansour, Michael A. Simpson, Helena Frysira, Anneke Maat-Kievit, Rick Van Minkelen, Jeanette M. Hoogeboom, Geert R. Mortier, Hannah Titheradge, Louise Brueton, Lois Starr, Zornitza Stark, Charlotte Ockeloen, Charles Marques Lourenco, Ed Blair & 9 others Emma Hobson, Jane Hurst, Isabelle Maystadt, Anne Destrée, Katta M. Girisha, Michelle Miller, Harry C. Dietz, Bart Loeys, Lut Van Laer

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.

Original languageEnglish
Pages (from-to)224-228
Number of pages5
JournalEuropean Journal of Human Genetics
Volume23
Issue number2
DOIs
Publication statusPublished - 20-02-2015

Fingerprint

Mutation
Loeys-Dietz Syndrome
Oncogene Proteins
Missense Mutation
Intellectual Disability
Connective Tissue
Exons
Observation
Shprintzen Golberg craniosynostosis
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Schepers, D., Doyle, A. J., Oswald, G., Sparks, E., Myers, L., Willems, P. J., ... Van Laer, L. (2015). The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. European Journal of Human Genetics, 23(2), 224-228. https://doi.org/10.1038/ejhg.2014.61
Schepers, Dorien ; Doyle, Alexander J. ; Oswald, Gretchen ; Sparks, Elizabeth ; Myers, Loretha ; Willems, Patrick J. ; Mansour, Sahar ; Simpson, Michael A. ; Frysira, Helena ; Maat-Kievit, Anneke ; Van Minkelen, Rick ; Hoogeboom, Jeanette M. ; Mortier, Geert R. ; Titheradge, Hannah ; Brueton, Louise ; Starr, Lois ; Stark, Zornitza ; Ockeloen, Charlotte ; Lourenco, Charles Marques ; Blair, Ed ; Hobson, Emma ; Hurst, Jane ; Maystadt, Isabelle ; Destrée, Anne ; Girisha, Katta M. ; Miller, Michelle ; Dietz, Harry C. ; Loeys, Bart ; Van Laer, Lut. / The SMAD-binding domain of SKI : A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. In: European Journal of Human Genetics. 2015 ; Vol. 23, No. 2. pp. 224-228.
@article{795ff7e3548342bfa25ceca7213c9f59,
title = "The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome",
abstract = "Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73{\%} (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.",
author = "Dorien Schepers and Doyle, {Alexander J.} and Gretchen Oswald and Elizabeth Sparks and Loretha Myers and Willems, {Patrick J.} and Sahar Mansour and Simpson, {Michael A.} and Helena Frysira and Anneke Maat-Kievit and {Van Minkelen}, Rick and Hoogeboom, {Jeanette M.} and Mortier, {Geert R.} and Hannah Titheradge and Louise Brueton and Lois Starr and Zornitza Stark and Charlotte Ockeloen and Lourenco, {Charles Marques} and Ed Blair and Emma Hobson and Jane Hurst and Isabelle Maystadt and Anne Destr{\'e}e and Girisha, {Katta M.} and Michelle Miller and Dietz, {Harry C.} and Bart Loeys and {Van Laer}, Lut",
year = "2015",
month = "2",
day = "20",
doi = "10.1038/ejhg.2014.61",
language = "English",
volume = "23",
pages = "224--228",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",
number = "2",

}

Schepers, D, Doyle, AJ, Oswald, G, Sparks, E, Myers, L, Willems, PJ, Mansour, S, Simpson, MA, Frysira, H, Maat-Kievit, A, Van Minkelen, R, Hoogeboom, JM, Mortier, GR, Titheradge, H, Brueton, L, Starr, L, Stark, Z, Ockeloen, C, Lourenco, CM, Blair, E, Hobson, E, Hurst, J, Maystadt, I, Destrée, A, Girisha, KM, Miller, M, Dietz, HC, Loeys, B & Van Laer, L 2015, 'The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome', European Journal of Human Genetics, vol. 23, no. 2, pp. 224-228. https://doi.org/10.1038/ejhg.2014.61

The SMAD-binding domain of SKI : A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. / Schepers, Dorien; Doyle, Alexander J.; Oswald, Gretchen; Sparks, Elizabeth; Myers, Loretha; Willems, Patrick J.; Mansour, Sahar; Simpson, Michael A.; Frysira, Helena; Maat-Kievit, Anneke; Van Minkelen, Rick; Hoogeboom, Jeanette M.; Mortier, Geert R.; Titheradge, Hannah; Brueton, Louise; Starr, Lois; Stark, Zornitza; Ockeloen, Charlotte; Lourenco, Charles Marques; Blair, Ed; Hobson, Emma; Hurst, Jane; Maystadt, Isabelle; Destrée, Anne; Girisha, Katta M.; Miller, Michelle; Dietz, Harry C.; Loeys, Bart; Van Laer, Lut.

In: European Journal of Human Genetics, Vol. 23, No. 2, 20.02.2015, p. 224-228.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The SMAD-binding domain of SKI

T2 - A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

AU - Schepers, Dorien

AU - Doyle, Alexander J.

AU - Oswald, Gretchen

AU - Sparks, Elizabeth

AU - Myers, Loretha

AU - Willems, Patrick J.

AU - Mansour, Sahar

AU - Simpson, Michael A.

AU - Frysira, Helena

AU - Maat-Kievit, Anneke

AU - Van Minkelen, Rick

AU - Hoogeboom, Jeanette M.

AU - Mortier, Geert R.

AU - Titheradge, Hannah

AU - Brueton, Louise

AU - Starr, Lois

AU - Stark, Zornitza

AU - Ockeloen, Charlotte

AU - Lourenco, Charles Marques

AU - Blair, Ed

AU - Hobson, Emma

AU - Hurst, Jane

AU - Maystadt, Isabelle

AU - Destrée, Anne

AU - Girisha, Katta M.

AU - Miller, Michelle

AU - Dietz, Harry C.

AU - Loeys, Bart

AU - Van Laer, Lut

PY - 2015/2/20

Y1 - 2015/2/20

N2 - Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.

AB - Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.

UR - http://www.scopus.com/inward/record.url?scp=84921416171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921416171&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2014.61

DO - 10.1038/ejhg.2014.61

M3 - Article

VL - 23

SP - 224

EP - 228

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 2

ER -