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

AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
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 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.
0022-2593
269-277
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Dewing, Jennifer M.
868fbf01-7b6e-499f-abf9-47409278373f
O'kelly, Ita
e640f28a-42f0-48a6-9ce2-cb5a85d08c66
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Gilbert, Rodney D.
a60642f2-761a-4a29-acad-2720db1d8ce9
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Seaby, Eleanor G.
a7290ab8-98ea-4093-9aa7-641d319d6064
Dewing, Jennifer M.
868fbf01-7b6e-499f-abf9-47409278373f
O'kelly, Ita
e640f28a-42f0-48a6-9ce2-cb5a85d08c66
Lachlan, Katherine
175ce889-ede8-477e-93eb-afefc1af5dda
Gilbert, Rodney D.
a60642f2-761a-4a29-acad-2720db1d8ce9
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Andreoletti, Gaia, Seaby, Eleanor G., Dewing, Jennifer M., O'kelly, Ita, Lachlan, Katherine, Gilbert, Rodney D. and Ennis, Sarah (2017) AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis Journal of Medical Genetics, 54, (4), pp. 269-277. (doi:10.1136/jmedgenet-2016-104100). (PMID:27811305).

Record type: Article

Abstract

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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Accepted/In Press date: 26 September 2016
e-pub ahead of print date: 3 November 2016
Published date: April 2017
Organisations: Human Development & Health

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Local EPrints ID: 402665
URI: http://eprints.soton.ac.uk/id/eprint/402665
ISSN: 0022-2593
PURE UUID: 68e20081-b5eb-47c5-8008-1960f9a30160

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Date deposited: 14 Nov 2016 12:44
Last modified: 17 Jul 2017 17:49

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Contributors

Author: Gaia Andreoletti
Author: Eleanor G. Seaby
Author: Jennifer M. Dewing
Author: Ita O'kelly
Author: Katherine Lachlan
Author: Rodney D. Gilbert
Author: Sarah Ennis

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