Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

Leen Abu-Safieh; Emad B. Abboud; Hisham Alkuraya; Hanan Shamseldin; Shamsa Al-Enzi; Lama Al-Abdi; Mais Hashem; Dilek Colak; Abdullah Jarallah; Hala Ahmad; Steve Bobis; Georges Nemer; Fadi Bitar; Fowzan S. Alkuraya

doi:10.1016/j.ajhg.2011.07.010

Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

Leen Abu-Safieh, Emad B. Abboud, Hisham Alkuraya, Hanan Shamseldin, Shamsa Al-Enzi, Lama Al-Abdi, Mais Hashem, Dilek Colak, Abdullah Jarallah, Hala Ahmad, Steve Bobis, Georges Nemer, Fadi Bitar, Fowzan S. Alkuraya^*

^*Corresponding author for this work

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

41 Citations (Scopus)

Abstract

Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.

Original language	English
Pages (from-to)	313-319
Number of pages	7
Journal	American Journal of Human Genetics
Volume	89
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2011.07.010
Publication status	Published - 12 Aug 2011
Externally published	Yes

Access to Document

10.1016/j.ajhg.2011.07.010

Cite this

Abu-Safieh, L., Abboud, E. B., Alkuraya, H., Shamseldin, H., Al-Enzi, S., Al-Abdi, L., Hashem, M., Colak, D., Jarallah, A., Ahmad, H., Bobis, S., Nemer, G., Bitar, F., & Alkuraya, F. S. (2011). Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms. American Journal of Human Genetics, 89(2), 313-319. https://doi.org/10.1016/j.ajhg.2011.07.010

@article{a8386d57db574afa9c3b206fda99f65a,

title = "Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms",

abstract = "Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.",

author = "Leen Abu-Safieh and Abboud, {Emad B.} and Hisham Alkuraya and Hanan Shamseldin and Shamsa Al-Enzi and Lama Al-Abdi and Mais Hashem and Dilek Colak and Abdullah Jarallah and Hala Ahmad and Steve Bobis and Georges Nemer and Fadi Bitar and Alkuraya, {Fowzan S.}",

year = "2011",

month = aug,

day = "12",

doi = "10.1016/j.ajhg.2011.07.010",

language = "English",

volume = "89",

pages = "313--319",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Abu-Safieh, L, Abboud, EB, Alkuraya, H, Shamseldin, H, Al-Enzi, S, Al-Abdi, L, Hashem, M, Colak, D, Jarallah, A, Ahmad, H, Bobis, S, Nemer, G, Bitar, F & Alkuraya, FS 2011, 'Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms', American Journal of Human Genetics, vol. 89, no. 2, pp. 313-319. https://doi.org/10.1016/j.ajhg.2011.07.010

TY - JOUR

T1 - Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

AU - Abu-Safieh, Leen

AU - Abboud, Emad B.

AU - Alkuraya, Hisham

AU - Shamseldin, Hanan

AU - Al-Enzi, Shamsa

AU - Al-Abdi, Lama

AU - Hashem, Mais

AU - Colak, Dilek

AU - Jarallah, Abdullah

AU - Ahmad, Hala

AU - Bobis, Steve

AU - Nemer, Georges

AU - Bitar, Fadi

AU - Alkuraya, Fowzan S.

PY - 2011/8/12

Y1 - 2011/8/12

N2 - Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.

AB - Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.

UR - http://www.scopus.com/inward/record.url?scp=80051631085&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2011.07.010

DO - 10.1016/j.ajhg.2011.07.010

M3 - Article

C2 - 21835307

AN - SCOPUS:80051631085

SN - 0002-9297

VL - 89

SP - 313

EP - 319

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

Abstract

Access to Document

Other files and links

Fingerprint

Cite this