Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies

TY - JOUR

T1 - Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies

AU - Kim, Hyung-Goo

AU - Kim, Hyun-Taek

AU - Leach, Natalia T

AU - Lan, Fei

AU - Ullmann, Reinhard

AU - Silahtaroglu, Asli

AU - Kurth, Ingo

AU - Nowka, Anja

AU - Seong, Ihn Sik

AU - Shen, Yiping

AU - Talkowski, Michael E

AU - Ruderfer, Douglas

AU - Lee, Ji-Hyun

AU - Glotzbach, Caron

AU - Ha, Kyungsoo

AU - Kjaergaard, Susanne

AU - Levin, Alex V

AU - Romeike, Bernd F

AU - Kleefstra, Tjitske

AU - Bartsch, Oliver

AU - Elsea, Sarah H

AU - Jabs, Ethylin Wang

AU - MacDonald, Marcy E

AU - Harris, David J

AU - Quade, Bradley J

AU - Ropers, Hans-Hilger

AU - Shaffer, Lisa G

AU - Kutsche, Kerstin

AU - Layman, Lawrence C

AU - Tommerup, Niels

AU - Kalscheuer, Vera M

AU - Shi, Yang

AU - Morton, Cynthia C

AU - Kim, Cheol-Hee

AU - Gusella, James F

N1 - Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2012/7/13

Y1 - 2012/7/13

N2 - Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function.

AB - Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function.

KW - Adolescent

KW - Adult

KW - Animals

KW - Child, Preschool

KW - Chromosome Deletion

KW - Chromosome Disorders

KW - Chromosomes, Human, Pair 11

KW - Craniofacial Abnormalities

KW - Female

KW - Genotype

KW - Haploinsufficiency

KW - Histone Deacetylases

KW - Humans

KW - Infant, Newborn

KW - Intellectual Disability

KW - Male

KW - Sodium Channels

KW - Translocation, Genetic

KW - Zebrafish

U2 - 10.1016/j.ajhg.2012.05.005

DO - 10.1016/j.ajhg.2012.05.005

M3 - Journal article

C2 - 22770980

SN - 0002-9297

VL - 91

SP - 56

EP - 72

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -