Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Diana Alcantara, Andrew E. Timms, Karen Gripp, Laura Baker, Kaylee Park, Sarah Collins, Chi Cheng, Fiona Stewart, Sarju G. Mehta, Anand Saggar, László Sztriha, Melinda Zombor, Oana Caluseriu, Ronit Mesterman, Margot I. Van Allen, Adeline Jacquinet, Sofia Ygberg, Jonathan A. Bernstein, Aaron M. Wenger, Harendra Guturu & 13 others Gill Bejerano, Natalia Gomez-Ospina, Anna Lehman, Enrico Alfei, Chiara Pantaleoni, Valerio Conti, Renzo Guerrini, Ute Moog, John M. Graham, Robert Hevner, William B. Dobyns, Mark O'Driscoll, Ghayda M. Mirzaa

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

Original languageEnglish
Pages (from-to)2610-2622
Number of pages13
JournalBrain
Volume140
Issue number10
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Megalencephaly
Mutation
Malformations of Cortical Development
Mosaicism
Phosphatidylinositol 3-Kinase
Brain
Genetic Association Studies
Phenotype
Genes
Phospholipids
Periventricular Nodular Heterotopia
Phosphotransferases

Keywords

  • AKT3
  • epilepsy
  • hemimegalencephaly
  • megalencephaly
  • polymicrogyria

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Alcantara, D., Timms, A. E., Gripp, K., Baker, L., Park, K., Collins, S., ... Mirzaa, G. M. (2017). Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain, 140(10), 2610-2622. https://doi.org/10.1093/brain/awx203

Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. / Alcantara, Diana; Timms, Andrew E.; Gripp, Karen; Baker, Laura; Park, Kaylee; Collins, Sarah; Cheng, Chi; Stewart, Fiona; Mehta, Sarju G.; Saggar, Anand; Sztriha, László; Zombor, Melinda; Caluseriu, Oana; Mesterman, Ronit; Van Allen, Margot I.; Jacquinet, Adeline; Ygberg, Sofia; Bernstein, Jonathan A.; Wenger, Aaron M.; Guturu, Harendra; Bejerano, Gill; Gomez-Ospina, Natalia; Lehman, Anna; Alfei, Enrico; Pantaleoni, Chiara; Conti, Valerio; Guerrini, Renzo; Moog, Ute; Graham, John M.; Hevner, Robert; Dobyns, William B.; O'Driscoll, Mark; Mirzaa, Ghayda M.

In: Brain, Vol. 140, No. 10, 01.01.2017, p. 2610-2622.

Research output: Contribution to journalArticle

Alcantara, D, Timms, AE, Gripp, K, Baker, L, Park, K, Collins, S, Cheng, C, Stewart, F, Mehta, SG, Saggar, A, Sztriha, L, Zombor, M, Caluseriu, O, Mesterman, R, Van Allen, MI, Jacquinet, A, Ygberg, S, Bernstein, JA, Wenger, AM, Guturu, H, Bejerano, G, Gomez-Ospina, N, Lehman, A, Alfei, E, Pantaleoni, C, Conti, V, Guerrini, R, Moog, U, Graham, JM, Hevner, R, Dobyns, WB, O'Driscoll, M & Mirzaa, GM 2017, 'Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly', Brain, vol. 140, no. 10, pp. 2610-2622. https://doi.org/10.1093/brain/awx203
Alcantara, Diana ; Timms, Andrew E. ; Gripp, Karen ; Baker, Laura ; Park, Kaylee ; Collins, Sarah ; Cheng, Chi ; Stewart, Fiona ; Mehta, Sarju G. ; Saggar, Anand ; Sztriha, László ; Zombor, Melinda ; Caluseriu, Oana ; Mesterman, Ronit ; Van Allen, Margot I. ; Jacquinet, Adeline ; Ygberg, Sofia ; Bernstein, Jonathan A. ; Wenger, Aaron M. ; Guturu, Harendra ; Bejerano, Gill ; Gomez-Ospina, Natalia ; Lehman, Anna ; Alfei, Enrico ; Pantaleoni, Chiara ; Conti, Valerio ; Guerrini, Renzo ; Moog, Ute ; Graham, John M. ; Hevner, Robert ; Dobyns, William B. ; O'Driscoll, Mark ; Mirzaa, Ghayda M. / Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. In: Brain. 2017 ; Vol. 140, No. 10. pp. 2610-2622.
@article{e499a87bb042409ca8b44bf34bfb6a57,
title = "Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly",
abstract = "Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.",
keywords = "AKT3, epilepsy, hemimegalencephaly, megalencephaly, polymicrogyria",
author = "Diana Alcantara and Timms, {Andrew E.} and Karen Gripp and Laura Baker and Kaylee Park and Sarah Collins and Chi Cheng and Fiona Stewart and Mehta, {Sarju G.} and Anand Saggar and L{\'a}szl{\'o} Sztriha and Melinda Zombor and Oana Caluseriu and Ronit Mesterman and {Van Allen}, {Margot I.} and Adeline Jacquinet and Sofia Ygberg and Bernstein, {Jonathan A.} and Wenger, {Aaron M.} and Harendra Guturu and Gill Bejerano and Natalia Gomez-Ospina and Anna Lehman and Enrico Alfei and Chiara Pantaleoni and Valerio Conti and Renzo Guerrini and Ute Moog and Graham, {John M.} and Robert Hevner and Dobyns, {William B.} and Mark O'Driscoll and Mirzaa, {Ghayda M.}",
note = "Extracted concepts Mutation Megalencephaly utation Brain Genes Malformations of Cortical Development",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/brain/awx203",
language = "English",
volume = "140",
pages = "2610--2622",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

AU - Alcantara, Diana

AU - Timms, Andrew E.

AU - Gripp, Karen

AU - Baker, Laura

AU - Park, Kaylee

AU - Collins, Sarah

AU - Cheng, Chi

AU - Stewart, Fiona

AU - Mehta, Sarju G.

AU - Saggar, Anand

AU - Sztriha, László

AU - Zombor, Melinda

AU - Caluseriu, Oana

AU - Mesterman, Ronit

AU - Van Allen, Margot I.

AU - Jacquinet, Adeline

AU - Ygberg, Sofia

AU - Bernstein, Jonathan A.

AU - Wenger, Aaron M.

AU - Guturu, Harendra

AU - Bejerano, Gill

AU - Gomez-Ospina, Natalia

AU - Lehman, Anna

AU - Alfei, Enrico

AU - Pantaleoni, Chiara

AU - Conti, Valerio

AU - Guerrini, Renzo

AU - Moog, Ute

AU - Graham, John M.

AU - Hevner, Robert

AU - Dobyns, William B.

AU - O'Driscoll, Mark

AU - Mirzaa, Ghayda M.

N1 - Extracted concepts Mutation Megalencephaly utation Brain Genes Malformations of Cortical Development

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

AB - Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

KW - AKT3

KW - epilepsy

KW - hemimegalencephaly

KW - megalencephaly

KW - polymicrogyria

UR - http://www.scopus.com/inward/record.url?scp=85030687641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030687641&partnerID=8YFLogxK

U2 - 10.1093/brain/awx203

DO - 10.1093/brain/awx203

M3 - Article

VL - 140

SP - 2610

EP - 2622

JO - Brain

JF - Brain

SN - 0006-8950

IS - 10

ER -