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Inactivation of AMMECR1 is associated with growth, bone and heart alterations

Inactivation of AMMECR1 is associated with growth, bone and heart alterations
Inactivation of AMMECR1 is associated with growth, bone and heart alterations
We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally-inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is co-expressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients’ features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart and kidney alterations with or without elliptocytosis.
1059-7794
281-291
Moysés-oliveira, Mariana
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Giannuzzi, Giuliana
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Fish, Richard J.
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Rosenfeld, Jill A.
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Petit, Florence
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De Fatima Soares, Maria
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Kulikowski, Leslie Domenici
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Battista, Adriana Di
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Zamariolli, Malú
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Xia, Fan
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Liehr, Thomas
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Kosyakova, Nadezda
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Carvalheira, Gianna
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Parker, Michael
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Seaby, Eleanor G.
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Ennis, Sarah
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Gilbert, Rodney D.
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Hagelstrom, R. Tanner
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Cremona, Maria L.
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Li, Wenhui L.
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Malhotra, Alka
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Chandrasekhar, Anjana
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Perry, Denise L.
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Taft, Ryan J.
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Mccarrier, Julie
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Basel, Donald G.
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Andrieux, Joris
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Stumpp, Taiza
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Antunes, Fernanda
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Pereira, Gustavo José
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Neerman-arbez, Marguerite
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Meloni, Vera Ayres
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Drummond-borg, Margaret
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Melaragno, Maria Isabel
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Reymond, Alexandre
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Moysés-oliveira, Mariana
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Giannuzzi, Giuliana
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Fish, Richard J.
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Rosenfeld, Jill A.
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Petit, Florence
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De Fatima Soares, Maria
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Kulikowski, Leslie Domenici
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Battista, Adriana Di
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Zamariolli, Malú
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Xia, Fan
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Liehr, Thomas
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Kosyakova, Nadezda
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Carvalheira, Gianna
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Parker, Michael
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Seaby, Eleanor G.
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Ennis, Sarah
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Gilbert, Rodney D.
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Hagelstrom, R. Tanner
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Cremona, Maria L.
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Li, Wenhui L.
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Malhotra, Alka
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Chandrasekhar, Anjana
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Perry, Denise L.
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Taft, Ryan J.
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Mccarrier, Julie
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Basel, Donald G.
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Andrieux, Joris
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Stumpp, Taiza
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Antunes, Fernanda
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Pereira, Gustavo José
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Neerman-arbez, Marguerite
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Meloni, Vera Ayres
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Drummond-borg, Margaret
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Melaragno, Maria Isabel
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Reymond, Alexandre
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Moysés-oliveira, Mariana, Giannuzzi, Giuliana, Fish, Richard J., Rosenfeld, Jill A., Petit, Florence, De Fatima Soares, Maria, Kulikowski, Leslie Domenici, Battista, Adriana Di, Zamariolli, Malú, Xia, Fan, Liehr, Thomas, Kosyakova, Nadezda, Carvalheira, Gianna, Parker, Michael, Seaby, Eleanor G., Ennis, Sarah, Gilbert, Rodney D., Hagelstrom, R. Tanner, Cremona, Maria L., Li, Wenhui L., Malhotra, Alka, Chandrasekhar, Anjana, Perry, Denise L., Taft, Ryan J., Mccarrier, Julie, Basel, Donald G., Andrieux, Joris, Stumpp, Taiza, Antunes, Fernanda, Pereira, Gustavo José, Neerman-arbez, Marguerite, Meloni, Vera Ayres, Drummond-borg, Margaret, Melaragno, Maria Isabel and Reymond, Alexandre (2018) Inactivation of AMMECR1 is associated with growth, bone and heart alterations Human Mutation, 39, (2), pp. 281-291. (doi:10.1002/humu.23373).

Record type: Article

Abstract

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally-inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is co-expressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients’ features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart and kidney alterations with or without elliptocytosis.

Text Moys-s-Oliveira_et_al-2017-Human_Mutation - Accepted Manuscript
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Accepted/In Press date: 18 November 2017
e-pub ahead of print date: 28 November 2017
Published date: 1 February 2018

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Local EPrints ID: 416257
URI: https://eprints.soton.ac.uk/id/eprint/416257
ISSN: 1059-7794
PURE UUID: 2ed7b108-78ed-49cd-b056-7760517b8b12

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Date deposited: 11 Dec 2017 17:30
Last modified: 20 Feb 2018 17:32

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Contributors

Author: Mariana Moysés-oliveira
Author: Giuliana Giannuzzi
Author: Richard J. Fish
Author: Jill A. Rosenfeld
Author: Florence Petit
Author: Maria De Fatima Soares
Author: Leslie Domenici Kulikowski
Author: Adriana Di Battista
Author: Malú Zamariolli
Author: Fan Xia
Author: Thomas Liehr
Author: Nadezda Kosyakova
Author: Gianna Carvalheira
Author: Michael Parker
Author: Eleanor G. Seaby
Author: Sarah Ennis
Author: Rodney D. Gilbert
Author: R. Tanner Hagelstrom
Author: Maria L. Cremona
Author: Wenhui L. Li
Author: Alka Malhotra
Author: Anjana Chandrasekhar
Author: Denise L. Perry
Author: Ryan J. Taft
Author: Julie Mccarrier
Author: Donald G. Basel
Author: Joris Andrieux
Author: Taiza Stumpp
Author: Fernanda Antunes
Author: Gustavo José Pereira
Author: Marguerite Neerman-arbez
Author: Vera Ayres Meloni
Author: Margaret Drummond-borg
Author: Maria Isabel Melaragno
Author: Alexandre Reymond

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