TY - JOUR
T1 - Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway
T2 - MPPH and MCAP
AU - Mirzaa, Ghayda M.
AU - Rivière, Jean Baptiste
AU - Dobyns, William B.
PY - 2013/5
Y1 - 2013/5
N2 - The megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental body overgrowth, among other features. MPPH, on the other hand, lacks consistent vascular or somatic manifestations besides postaxial polydactyly in almost half of reported individuals. We identified de novo germline mutations in PIK3R2 and AKT3 in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations in PIK3CA in individuals with MCAP. PIK3R2, AKT3, and PIK3CA are members of the critical phosphatidylinositol-3-kinase (PI3K)-vakt murine thymoma viral oncogene homolog (AKT) pathway that is well implicated in cell growth, proliferation, survival, apoptosis, among other diverse cellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K-AKT pathway. Germline and postzygotic mutations of PIK3CA and other PI3K-AKT-mTOR pathway genes have also been identified in several other overgrowth syndromes, highlighting the key role of this signaling pathway in normal development and pathophysiology of a large group of congenital anomalies.
AB - The megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental body overgrowth, among other features. MPPH, on the other hand, lacks consistent vascular or somatic manifestations besides postaxial polydactyly in almost half of reported individuals. We identified de novo germline mutations in PIK3R2 and AKT3 in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations in PIK3CA in individuals with MCAP. PIK3R2, AKT3, and PIK3CA are members of the critical phosphatidylinositol-3-kinase (PI3K)-vakt murine thymoma viral oncogene homolog (AKT) pathway that is well implicated in cell growth, proliferation, survival, apoptosis, among other diverse cellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K-AKT pathway. Germline and postzygotic mutations of PIK3CA and other PI3K-AKT-mTOR pathway genes have also been identified in several other overgrowth syndromes, highlighting the key role of this signaling pathway in normal development and pathophysiology of a large group of congenital anomalies.
KW - AKT3
KW - Capillary malformations
KW - Megalencephaly
KW - Mosaicism
KW - Overgrowth
KW - PI3K-AKT pathway
KW - PIK3CA
KW - PIK3R2
KW - Polymicrogyria
UR - http://www.scopus.com/inward/record.url?scp=84876806696&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876806696&partnerID=8YFLogxK
U2 - 10.1002/ajmg.c.31361
DO - 10.1002/ajmg.c.31361
M3 - Article
C2 - 23592320
AN - SCOPUS:84876806696
SN - 1552-4868
VL - 163
SP - 122
EP - 130
JO - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics
JF - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics
IS - 2
ER -