PMID- 34048549
OWN - NLM
STAT- MEDLINE
DCOM- 20211214
LR  - 20220716
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Print)
IS  - 0006-8950 (Linking)
VI  - 144
IP  - 10
DP  - 2021 Nov 29
TI  - PTEN somatic mutations contribute to spectrum of cerebral overgrowth.
PG  - 2971-2978
LID - 10.1093/brain/awab173 [doi]
AB  - Phosphatase and tensin homologue (PTEN) regulates cell growth and survival 
      through inhibition of the mammalian target of rapamycin (MTOR) signalling 
      pathway. Germline genetic variation of PTEN is associated with autism, 
      macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental 
      PTEN somatic mutations on nervous system phenotypes is not well understood, 
      although brain somatic mosaicism of MTOR pathway genes is an emerging cause of 
      cortical dysplasia and epilepsy in the paediatric population. Here we report two 
      somatic variants of PTEN affecting a single patient presenting with intractable 
      epilepsy and hemimegalencephaly that varied in clinical severity throughout the 
      left cerebral hemisphere. High-throughput sequencing analysis of affected brain 
      tissue identified two somatic variants in PTEN. The first variant was present in 
      multiple cell lineages throughout the entire hemisphere and associated with mild 
      cerebral overgrowth. The second variant was restricted to posterior brain regions 
      and affected the opposite PTEN allele, resulting in a segmental region of more 
      severe malformation, and the only neurons in which it was found by single-nuclei 
      RNA-sequencing had a unique disease-related expression profile. This study 
      reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and 
      furthermore demonstrates the varying effects of single- or bi-allelic disruption 
      of PTEN on cortical phenotypes.
CI  - (c) The Author(s) (2021). Published by Oxford University Press on behalf of the 
      Guarantors of Brain. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Koboldt, Daniel C
AU  - Koboldt DC
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Miller, Katherine E
AU  - Miller KE
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Miller, Anthony R
AU  - Miller AR
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Bush, Jocelyn M
AU  - Bush JM
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - McGrath, Sean
AU  - McGrath S
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Leraas, Kristen
AU  - Leraas K
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Crist, Erin
AU  - Crist E
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, 
      Columbus, OH, USA.
FAU - Fair, Summer
AU  - Fair S
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Schwind, Wesley
AU  - Schwind W
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Wijeratne, Saranga
AU  - Wijeratne S
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Fitch, James
AU  - Fitch J
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Leonard, Jeffrey
AU  - Leonard J
AD  - Department of Neurosurgery, Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Neurosurgery, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Shaikhouni, Ammar
AU  - Shaikhouni A
AD  - Department of Neurosurgery, Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Neurosurgery, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Hester, Mark E
AU  - Hester ME
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
AD  - Department of Neuroscience, The Ohio State University Wexner Medical Center, 
      Columbus, OH, USA.
FAU - Magrini, Vincent
AU  - Magrini V
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Ho, Mai-Lan
AU  - Ho ML
AD  - Department of Radiology, Nationwide Children's Hospital and The Ohio State 
      University College of Medicine, Columbus, OH, USA.
FAU - Pierson, Christopher R
AU  - Pierson CR
AD  - Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, 
      Columbus, OH, USA.
AD  - Department of Pathology, The Ohio State University College of Medicine, Columbus, 
      OH, USA.
AD  - Department of Biomedical Education and Anatomy, Division of Anatomy, The Ohio 
      State University College of Medicine, Columbus, OH, USA.
FAU - Wilson, Richard K
AU  - Wilson RK
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Ostendorf, Adam P
AU  - Ostendorf AP
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
AD  - Department of Neurosurgery, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
AD  - Division of Child Neurology, Nationwide Children's Hospital, Columbus, OH, USA.
FAU - Mardis, Elaine R
AU  - Mardis ER
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
AD  - Department of Neurosurgery, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
FAU - Bedrosian, Tracy A
AU  - Bedrosian TA
AUID- ORCID: 0000-0002-9455-1350
AD  - The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner 
      Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
LA  - eng
GR  - K01 HG011062/HG/NHGRI NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Cerebral Cortex/*diagnostic imaging/surgery
MH  - Genetic Variation/*genetics
MH  - Hemimegalencephaly/*diagnostic imaging/*genetics/surgery
MH  - Humans
MH  - Infant
MH  - Male
MH  - Mutation/*genetics
MH  - PTEN Phosphohydrolase/*genetics
PMC - PMC8634064
OTO - NOTNLM
OT  - brain development
OT  - epilepsy
OT  - hemimegalencephaly (HME)
OT  - somatic mosaicism
EDAT- 2021/05/29 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/05/28
CRDT- 2021/05/28 17:27
PHST- 2021/02/08 00:00 [received]
PHST- 2021/03/26 00:00 [revised]
PHST- 2021/04/13 00:00 [accepted]
PHST- 2021/05/29 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/05/28 17:27 [entrez]
PHST- 2022/05/28 00:00 [pmc-release]
AID - 6287649 [pii]
AID - awab173 [pii]
AID - 10.1093/brain/awab173 [doi]
PST - ppublish
SO  - Brain. 2021 Nov 29;144(10):2971-2978. doi: 10.1093/brain/awab173.