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AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis

BACKGROUND: Deletions in the Xq22.3–Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical...

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Autores principales: Andreoletti, Gaia, Seaby, Eleanor G, Dewing, Jennifer M, O'Kelly, Ita, Lachlan, Katherine, Gilbert, Rodney D, Ennis, Sarah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502304/
https://www.ncbi.nlm.nih.gov/pubmed/27811305
http://dx.doi.org/10.1136/jmedgenet-2016-104100
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author Andreoletti, Gaia
Seaby, Eleanor G
Dewing, Jennifer M
O'Kelly, Ita
Lachlan, Katherine
Gilbert, Rodney D
Ennis, Sarah
author_facet Andreoletti, Gaia
Seaby, Eleanor G
Dewing, Jennifer M
O'Kelly, Ita
Lachlan, Katherine
Gilbert, Rodney D
Ennis, Sarah
author_sort Andreoletti, Gaia
collection PubMed
description BACKGROUND: Deletions in the Xq22.3–Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula. METHODS: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein. RESULTS: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother. CONCLUSIONS: Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.
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spelling pubmed-55023042017-07-11 AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis Andreoletti, Gaia Seaby, Eleanor G Dewing, Jennifer M O'Kelly, Ita Lachlan, Katherine Gilbert, Rodney D Ennis, Sarah J Med Genet New Loci BACKGROUND: Deletions in the Xq22.3–Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula. METHODS: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein. RESULTS: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother. CONCLUSIONS: Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate. BMJ Publishing Group 2017-04 2016-11-03 /pmc/articles/PMC5502304/ /pubmed/27811305 http://dx.doi.org/10.1136/jmedgenet-2016-104100 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
spellingShingle New Loci
Andreoletti, Gaia
Seaby, Eleanor G
Dewing, Jennifer M
O'Kelly, Ita
Lachlan, Katherine
Gilbert, Rodney D
Ennis, Sarah
AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title_full AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title_fullStr AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title_full_unstemmed AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title_short AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
title_sort ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
topic New Loci
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502304/
https://www.ncbi.nlm.nih.gov/pubmed/27811305
http://dx.doi.org/10.1136/jmedgenet-2016-104100
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