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

Hyung Goo Kim, Hyun Taek Kim, Natalia T. Leach, Fei Lan, Reinhard Ullmann, Asli Silahtaroglu, Ingo Kurth, Anja Nowka, Ihn Sik Seong, Yiping Shen, Michael E. Talkowski, Douglas Ruderfer, Ji Hyun Lee, Caron Glotzbach, Kyungsoo Ha, Susanne Kjaergaard, Alex V. Levin, Bernd F. Romeike, Tjitske Kleefstra, Oliver Bartsch & 15 others Sarah H. Elsea, Ethylin Wang Jabs, Marcy E. MacDonald, David J. Harris, Bradley J. Quade, Hans Hilger Ropers, Lisa G. Shaffer, Kerstin Kutsche, Lawrence C Layman, Niels Tommerup, Vera M. Kalscheuer, Yang Shi, Cynthia C. Morton, Cheol Hee Kim, James F. Gusella

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)56-72
Number of pages17
JournalAmerican Journal of Human Genetics
Volume91
Issue number1
DOIs
StatePublished - Jul 13 2012

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Intellectual Disability
Genes
Multiple Hereditary Exostoses
Haploinsufficiency
Lysine
Craniofacial Abnormalities
Phenotype
Homeodomain Proteins
Plant Proteins
Chromosomes, Human, Pair 11
Histone Deacetylases
Chromatin Assembly and Disassembly
Zebrafish
Potocki-Shaffer syndrome
Cognition
Apoptosis
Cell Line
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. / Kim, Hyung Goo; Kim, Hyun Taek; Leach, Natalia T.; Lan, Fei; Ullmann, Reinhard; Silahtaroglu, Asli; Kurth, Ingo; Nowka, Anja; Seong, Ihn Sik; Shen, Yiping; Talkowski, Michael E.; Ruderfer, Douglas; Lee, Ji Hyun; Glotzbach, Caron; Ha, Kyungsoo; Kjaergaard, Susanne; Levin, Alex V.; Romeike, Bernd F.; Kleefstra, Tjitske; Bartsch, Oliver; Elsea, Sarah H.; Jabs, Ethylin Wang; MacDonald, Marcy E.; Harris, David J.; Quade, Bradley J.; Ropers, Hans Hilger; Shaffer, Lisa G.; Kutsche, Kerstin; Layman, Lawrence C; Tommerup, Niels; Kalscheuer, Vera M.; Shi, Yang; Morton, Cynthia C.; Kim, Cheol Hee; Gusella, James F.

In: American Journal of Human Genetics, Vol. 91, No. 1, 13.07.2012, p. 56-72.

Research output: Contribution to journalArticle

Kim, HG, Kim, HT, Leach, NT, Lan, F, Ullmann, R, Silahtaroglu, A, Kurth, I, Nowka, A, Seong, IS, Shen, Y, Talkowski, ME, Ruderfer, D, Lee, JH, Glotzbach, C, Ha, K, Kjaergaard, S, Levin, AV, Romeike, BF, Kleefstra, T, Bartsch, O, Elsea, SH, Jabs, EW, MacDonald, ME, Harris, DJ, Quade, BJ, Ropers, HH, Shaffer, LG, Kutsche, K, Layman, LC, Tommerup, N, Kalscheuer, VM, Shi, Y, Morton, CC, Kim, CH & Gusella, JF 2012, 'Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies', American Journal of Human Genetics, vol. 91, no. 1, pp. 56-72. https://doi.org/10.1016/j.ajhg.2012.05.005
Kim, Hyung Goo ; Kim, Hyun Taek ; Leach, Natalia T. ; Lan, Fei ; Ullmann, Reinhard ; Silahtaroglu, Asli ; Kurth, Ingo ; Nowka, Anja ; Seong, Ihn Sik ; Shen, Yiping ; Talkowski, Michael E. ; Ruderfer, Douglas ; Lee, Ji Hyun ; Glotzbach, Caron ; Ha, Kyungsoo ; Kjaergaard, Susanne ; Levin, Alex V. ; Romeike, Bernd F. ; Kleefstra, Tjitske ; Bartsch, Oliver ; Elsea, Sarah H. ; Jabs, Ethylin Wang ; MacDonald, Marcy E. ; Harris, David J. ; Quade, Bradley J. ; Ropers, Hans Hilger ; Shaffer, Lisa G. ; Kutsche, Kerstin ; Layman, Lawrence C ; Tommerup, Niels ; Kalscheuer, Vera M. ; Shi, Yang ; Morton, Cynthia C. ; Kim, Cheol Hee ; Gusella, James F. / Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 1. pp. 56-72.
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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.",
author = "Kim, {Hyung Goo} and Kim, {Hyun Taek} and Leach, {Natalia T.} and Fei Lan and Reinhard Ullmann and Asli Silahtaroglu and Ingo Kurth and Anja Nowka and Seong, {Ihn Sik} and Yiping Shen and Talkowski, {Michael E.} and Douglas Ruderfer and Lee, {Ji Hyun} and Caron Glotzbach and Kyungsoo Ha and Susanne Kjaergaard and Levin, {Alex V.} and Romeike, {Bernd F.} and Tjitske Kleefstra and Oliver Bartsch and Elsea, {Sarah H.} and Jabs, {Ethylin Wang} and MacDonald, {Marcy E.} and Harris, {David J.} and Quade, {Bradley J.} and Ropers, {Hans Hilger} and Shaffer, {Lisa G.} and Kerstin Kutsche and Layman, {Lawrence C} and Niels Tommerup and Kalscheuer, {Vera M.} and Yang Shi and Morton, {Cynthia C.} and Kim, {Cheol Hee} and Gusella, {James F.}",
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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.

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.

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