title: Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies.
abstract: 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.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA. hkim@chgr.mgh.harvard.edu
authors: Hyung-Goo
authors: HG
authors: Kim
authors: Hyun-Taek
authors: HT
authors: Kim
authors: Natalia T
authors: NT
authors: Leach
authors: Fei
authors: F
authors: Lan
authors: Reinhard
authors: R
authors: Ullmann
authors: Asli
authors: A
authors: Silahtaroglu
authors: Ingo
authors: I
authors: Kurth
authors: Anja
authors: A
authors: Nowka
authors: Ihn Sik
authors: IS
authors: Seong
authors: Yiping
authors: Y
authors: Shen
authors: Michael E
authors: ME
authors: Talkowski
authors: Douglas
authors: D
authors: Ruderfer
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Caron
authors: C
authors: Glotzbach
authors: Kyungsoo
authors: K
authors: Ha
authors: Susanne
authors: S
authors: Kjaergaard
authors: Alex V
authors: AV
authors: Levin
authors: Bernd F
authors: BF
authors: Romeike
authors: Tjitske
authors: T
authors: Kleefstra
authors: Oliver
authors: O
authors: Bartsch
authors: Sarah H
authors: SH
authors: Elsea
authors: Ethylin Wang
authors: EW
authors: Jabs
authors: Marcy E
authors: ME
authors: MacDonald
authors: David J
authors: DJ
authors: Harris
authors: Bradley J
authors: BJ
authors: Quade
authors: Hans-Hilger
authors: HH
authors: Ropers
authors: Lisa G
authors: LG
authors: Shaffer
authors: Kerstin
authors: K
authors: Kutsche
authors: Lawrence C
authors: LC
authors: Layman
authors: Niels
authors: N
authors: Tommerup
authors: Vera M
authors: VM
authors: Kalscheuer
authors: Yang
authors: Y
authors: Shi
authors: Cynthia C
authors: CC
authors: Morton
authors: Cheol-Hee
authors: CH
authors: Kim
authors: James F
authors: JF
authors: Gusella
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D005097:Exostoses, Multiple Hereditary; D005260:Female; D005838:Genotype; D057895:Haploinsufficiency; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D062552:NAV1.3 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics; D014178:Translocation, Genetic; D015027:Zebrafish
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; C424715:SCN3A protein, human; D015222:Sodium Channels; C492634:PHF21A protein, human; D006655:Histone Deacetylases