Molecular causes of the cardio-facio-cutaneous syndrome

W. E. Tidyman, Katherine A Rauen

Research output: Chapter in Book/Report/Conference proceedingChapter

8 Citations (Scopus)

Abstract

Cardio-facio-cutaneous (CFC) syndrome is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases B-Raf, MEK1 or MEK2. Mutations in K-Ras, a small GTPase, have also been implicated as causing CFC syndrome and Noonan syndrome, however its role has yet to be well defined. In those individuals who are found to have a mutation, the majority occur in BRAF, whereas, mutations in MEK1 or MEK2 comprise about 27%. Functional studies of these novel CFC mutant proteins demonstrate that B-Raf may be activated or kinase impaired, whereas all the MEK mutant proteins studied to date demonstrate increased activity. Since CFC syndrome may have a progressive, evolving phenotype, the possible use of systemic therapies to reduce MAPK activity may be of great benefit to this population of patients and certainly warrants investigation. However, animal studies on the effects of MAPK inhibitors will be essential because of the critical role this pathway plays during development.

Original languageEnglish (US)
Title of host publicationNoonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling
Pages73-82
Number of pages10
Volume17
DOIs
StatePublished - 2009

Publication series

NameMonographs in Human Genetics
Volume17
ISSN (Print)00770876
ISSN (Electronic)16623835

Fingerprint

Mitogen-Activated Protein Kinases
Mutation
Mutant Proteins
Noonan Syndrome
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Proto-Oncogene Proteins c-akt
Skin
Muscle Hypotonia
Critical Pathways
Monomeric GTP-Binding Proteins
Mitogen-Activated Protein Kinase Kinases
Protein Kinase Inhibitors
Phosphotransferases
Phenotype
Cardiofaciocutaneous syndrome
Population
Therapeutics

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Tidyman, W. E., & Rauen, K. A. (2009). Molecular causes of the cardio-facio-cutaneous syndrome. In Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling (Vol. 17, pp. 73-82). (Monographs in Human Genetics; Vol. 17). https://doi.org/10.1159/000164843

Molecular causes of the cardio-facio-cutaneous syndrome. / Tidyman, W. E.; Rauen, Katherine A.

Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. Vol. 17 2009. p. 73-82 (Monographs in Human Genetics; Vol. 17).

Research output: Chapter in Book/Report/Conference proceedingChapter

Tidyman, WE & Rauen, KA 2009, Molecular causes of the cardio-facio-cutaneous syndrome. in Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. vol. 17, Monographs in Human Genetics, vol. 17, pp. 73-82. https://doi.org/10.1159/000164843
Tidyman WE, Rauen KA. Molecular causes of the cardio-facio-cutaneous syndrome. In Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. Vol. 17. 2009. p. 73-82. (Monographs in Human Genetics). https://doi.org/10.1159/000164843
Tidyman, W. E. ; Rauen, Katherine A. / Molecular causes of the cardio-facio-cutaneous syndrome. Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. Vol. 17 2009. pp. 73-82 (Monographs in Human Genetics).
@inbook{ed9729b335a74da0938c1f3b36416f9d,
title = "Molecular causes of the cardio-facio-cutaneous syndrome",
abstract = "Cardio-facio-cutaneous (CFC) syndrome is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases B-Raf, MEK1 or MEK2. Mutations in K-Ras, a small GTPase, have also been implicated as causing CFC syndrome and Noonan syndrome, however its role has yet to be well defined. In those individuals who are found to have a mutation, the majority occur in BRAF, whereas, mutations in MEK1 or MEK2 comprise about 27{\%}. Functional studies of these novel CFC mutant proteins demonstrate that B-Raf may be activated or kinase impaired, whereas all the MEK mutant proteins studied to date demonstrate increased activity. Since CFC syndrome may have a progressive, evolving phenotype, the possible use of systemic therapies to reduce MAPK activity may be of great benefit to this population of patients and certainly warrants investigation. However, animal studies on the effects of MAPK inhibitors will be essential because of the critical role this pathway plays during development.",
author = "Tidyman, {W. E.} and Rauen, {Katherine A}",
year = "2009",
doi = "10.1159/000164843",
language = "English (US)",
isbn = "9783805586535",
volume = "17",
series = "Monographs in Human Genetics",
pages = "73--82",
booktitle = "Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling",

}

TY - CHAP

T1 - Molecular causes of the cardio-facio-cutaneous syndrome

AU - Tidyman, W. E.

AU - Rauen, Katherine A

PY - 2009

Y1 - 2009

N2 - Cardio-facio-cutaneous (CFC) syndrome is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases B-Raf, MEK1 or MEK2. Mutations in K-Ras, a small GTPase, have also been implicated as causing CFC syndrome and Noonan syndrome, however its role has yet to be well defined. In those individuals who are found to have a mutation, the majority occur in BRAF, whereas, mutations in MEK1 or MEK2 comprise about 27%. Functional studies of these novel CFC mutant proteins demonstrate that B-Raf may be activated or kinase impaired, whereas all the MEK mutant proteins studied to date demonstrate increased activity. Since CFC syndrome may have a progressive, evolving phenotype, the possible use of systemic therapies to reduce MAPK activity may be of great benefit to this population of patients and certainly warrants investigation. However, animal studies on the effects of MAPK inhibitors will be essential because of the critical role this pathway plays during development.

AB - Cardio-facio-cutaneous (CFC) syndrome is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases B-Raf, MEK1 or MEK2. Mutations in K-Ras, a small GTPase, have also been implicated as causing CFC syndrome and Noonan syndrome, however its role has yet to be well defined. In those individuals who are found to have a mutation, the majority occur in BRAF, whereas, mutations in MEK1 or MEK2 comprise about 27%. Functional studies of these novel CFC mutant proteins demonstrate that B-Raf may be activated or kinase impaired, whereas all the MEK mutant proteins studied to date demonstrate increased activity. Since CFC syndrome may have a progressive, evolving phenotype, the possible use of systemic therapies to reduce MAPK activity may be of great benefit to this population of patients and certainly warrants investigation. However, animal studies on the effects of MAPK inhibitors will be essential because of the critical role this pathway plays during development.

UR - http://www.scopus.com/inward/record.url?scp=68649085816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68649085816&partnerID=8YFLogxK

U2 - 10.1159/000164843

DO - 10.1159/000164843

M3 - Chapter

AN - SCOPUS:68649085816

SN - 9783805586535

VL - 17

T3 - Monographs in Human Genetics

SP - 73

EP - 82

BT - Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling

ER -