Abstract
Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/ mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1, or MEK2. CFC is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic features, cardiac defects, ectodermal anomalies and developmental delay.We report a 71/2-month-old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C→Atransversion in exon 3 resulting in a nonsynonymous missense substitution, p.P128Q. Other family members, including the proband's mother and half-sibling, displayed phenotypic features of CFC and were also screened for the MEK2 mutation identified in the proband. Sorting Intolerant From Tolerant (SIFT) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of HEK 293T cells with subsequent Western analysis was used to demonstrate increased kinase activity, as measured by ERK phosphorylation. This first reported case of a vertically transmitted functional CFC MEK mutation further expands our understanding of germline mutations within the Ras/MAPK pathway.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 807-814 |
| Number of pages | 8 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 152 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2010 |
| Externally published | Yes |
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Keywords
- Acute lymphoblastic leukemia
- Autosomal dominant
- BRAF
- Cardio-facio-cutaneous syndrome
- MEK1
- MEK2
- Multiple generation transmission
- Ras/MAPK
- RASopathy
- Signal transduction pathway
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome : Transmission through four generations. / Rauen, Katherine A; Tidyman, William E.; Estep, Anne L.; Sampath, Srirangan; Peltier, Henry M.; Bale, Sherri J.; Lacassie, Yves.
In: American Journal of Medical Genetics, Part A, Vol. 152, No. 4, 04.2010, p. 807-814.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome
T2 - Transmission through four generations
AU - Rauen, Katherine A
AU - Tidyman, William E.
AU - Estep, Anne L.
AU - Sampath, Srirangan
AU - Peltier, Henry M.
AU - Bale, Sherri J.
AU - Lacassie, Yves
PY - 2010/4
Y1 - 2010/4
N2 - Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/ mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1, or MEK2. CFC is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic features, cardiac defects, ectodermal anomalies and developmental delay.We report a 71/2-month-old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C→Atransversion in exon 3 resulting in a nonsynonymous missense substitution, p.P128Q. Other family members, including the proband's mother and half-sibling, displayed phenotypic features of CFC and were also screened for the MEK2 mutation identified in the proband. Sorting Intolerant From Tolerant (SIFT) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of HEK 293T cells with subsequent Western analysis was used to demonstrate increased kinase activity, as measured by ERK phosphorylation. This first reported case of a vertically transmitted functional CFC MEK mutation further expands our understanding of germline mutations within the Ras/MAPK pathway.
AB - Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/ mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1, or MEK2. CFC is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic features, cardiac defects, ectodermal anomalies and developmental delay.We report a 71/2-month-old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C→Atransversion in exon 3 resulting in a nonsynonymous missense substitution, p.P128Q. Other family members, including the proband's mother and half-sibling, displayed phenotypic features of CFC and were also screened for the MEK2 mutation identified in the proband. Sorting Intolerant From Tolerant (SIFT) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of HEK 293T cells with subsequent Western analysis was used to demonstrate increased kinase activity, as measured by ERK phosphorylation. This first reported case of a vertically transmitted functional CFC MEK mutation further expands our understanding of germline mutations within the Ras/MAPK pathway.
KW - Acute lymphoblastic leukemia
KW - Autosomal dominant
KW - BRAF
KW - Cardio-facio-cutaneous syndrome
KW - MEK1
KW - MEK2
KW - Multiple generation transmission
KW - Ras/MAPK
KW - RASopathy
KW - Signal transduction pathway
UR - http://www.scopus.com/inward/record.url?scp=77950409870&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950409870&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.33342
DO - 10.1002/ajmg.a.33342
M3 - Article
C2 - 20358587
AN - SCOPUS:77950409870
VL - 152
SP - 807
EP - 814
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
SN - 1552-4825
IS - 4
ER -