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; 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

doi:10.1016/j.ajhg.2012.05.005

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 BartschSarah 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

Department of Cellular and Molecular Medicine

37 Citations (Scopus)

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 language	English
Journal	American Journal of Human Genetics
Volume	91
Issue number	1
Pages (from-to)	56-72
Number of pages	17
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2012.05.005
Publication status	Published - 13 Jul 2012

Keywords

Adolescent
Adult
Animals
Child, Preschool
Chromosome Deletion
Chromosome Disorders
Chromosomes, Human, Pair 11
Craniofacial Abnormalities
Female
Genotype
Haploinsufficiency
Histone Deacetylases
Humans
Infant, Newborn
Intellectual Disability
Male
Sodium Channels
Translocation, Genetic
Zebrafish

Access to Document

10.1016/j.ajhg.2012.05.005

Cite this

Kim, H.-G., Kim, H.-T., Leach, N. T., Lan, F., Ullmann, R., Silahtaroglu, A., Kurth, I., Nowka, A., Seong, I. S., Shen, Y., Talkowski, M. E., Ruderfer, D., Lee, J.-H., Glotzbach, C., Ha, K., Kjaergaard, S., Levin, A. V., Romeike, B. F., Kleefstra, T., ... Gusella, J. F. (2012). Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. American Journal of Human Genetics, 91(1), 56-72. https://doi.org/10.1016/j.ajhg.2012.05.005

Kim, H-G, Kim, H-T, Leach, NT, Lan, F, Ullmann, R, Silahtaroglu, A, Kurth, I, Nowka, A, Seong, IS, Shen, Y, Talkowski, ME, Ruderfer, D, Lee, J-H, 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, H-H, Shaffer, LG, Kutsche, K, Layman, LC, Tommerup, N, Kalscheuer, VM, Shi, Y, Morton, CC, Kim, C-H & 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

@article{0b84887ac43144e9ad40a65bd266c750,

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.",

keywords = "Adolescent, Adult, Animals, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 11, Craniofacial Abnormalities, Female, Genotype, Haploinsufficiency, Histone Deacetylases, Humans, Infant, Newborn, Intellectual Disability, Male, Sodium Channels, Translocation, Genetic, Zebrafish",

author = "Hyung-Goo Kim and Hyun-Taek Kim 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 Ji-Hyun Lee 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 Hans-Hilger Ropers 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 Cheol-Hee Kim and Gusella, {James F}",

year = "2012",

month = jul,

day = "13",

doi = "10.1016/j.ajhg.2012.05.005",

language = "English",

volume = "91",

pages = "56--72",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

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

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 -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this