Format

Send to

Choose Destination
Hum Mutat. 2018 Feb;39(2):281-291. doi: 10.1002/humu.23373. Epub 2017 Dec 14.

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

Author information

1
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
2
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
3
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
5
Clinique de Génétique, CHU Lille - Hôpital Jeanne de Flandre, Lille, France.
6
Psychobiology Department, Universidade Federal de São Paulo, São Paulo, Brazil.
7
Department of Pathology, Laboratório de Citogenômica, LIM 03, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
8
Universitätsklinikum Jena, Institut für Humangenetik, Jena, Germany.
9
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
10
Genomic Informatics Group, University Hospital Southampton, Southampton, United Kingdom.
11
Southampton Children's Hospital, University Hospital Southampton, Southampton, United Kingdom.
12
Illumina Clinical Services Laboratory, San Diego, California.
13
Department of Pediatrics, Section of Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
14
Institut de Génétique Médicale, CHU Lille - Hôpital Jeanne de Flandre, Lille, France.
15
Developmental Biology Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
16
Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.
17
Cook Children's Genetic Clinic, Fort Worth, Texas.

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 coexpressed 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.

KEYWORDS:

AMMECR1; X-linked disease; bone dysplasia; growth delay; heart alteration

PMID:
29193635
DOI:
10.1002/humu.23373
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center