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

被引:11
作者
Andreoletti, Gaia [1 ]
Seaby, Eleanor G. [1 ]
Dewing, Jennifer M. [2 ]
O'Kelly, Ita [2 ]
Lachlan, Katherine [1 ,3 ]
Gilbert, Rodney D. [4 ]
Ennis, Sarah [1 ]
机构
[1] Univ Southampton, Southampton Gen Hosp, Human Genet & Genomic Med, Duthie Bldg Mailpoint 808, Southampton, Hants, England
[2] Univ Southampton, Southampton Gen Hosp, Ctr Human Dev Stem Cells & Regenerat HDH, IDS Bldg, Southampton, Hants, England
[3] Univ Hosp Southampton NHS Fdn Trust, Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England
[4] Southampton Childerns Hosp, Wessex Reg Paediat Nephrourol Serv, Southampton, Hants, England
基金
英国生物技术与生命科学研究理事会;
关键词
MENTAL-RETARDATION; ALPORT-SYNDROME; DELETION; DISEASE; GENE;
D O I
10.1136/jmedgenet-2016-104100
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:269 / 277
页数:9
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