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

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Moyses-Oliveira, Mariana ^{[1, 2]} ; Giannuzzi, Giuliana ^[2] ; Fish, Richard J. ^[3] ; Rosenfeld, Jill A. ^[4] ; Petit, Florence ^[5] ; Soares, Maria de Fatima ^[6] ; Kulikowski, Leslie Domenici ^[7] ; Di-Battista, Adriana ^[1] ; Zamariolli, Malu ^[1] ; Xia, Fan ; Liehr, Thomas ^[8] ; Kosyakova, Nadezda ^[8] ; Carvalheira, Gianna ^[1] ; Parker, Michael ^[9] ; Seaby, Eleanor G. ^[10] ; Ennis, Sarah ^[10] ; Gilbert, Rodney D. ^[11] ; Hagelstrom, R. Tanner ^[12] ; Cremona, Maria L. ^[12] ; Li, Wenhui L. ^[12] ; Malhotra, Alka ^[12] ; Chandrasekhar, Anjana ^[12] ; Perry, Denise L. ^[12] ; Taft, Ryan J. ^[12] ; McCarrier, Julie ^[13] ; Basel, Donald G. ^[13] ; Andrieux, Joris ^[14] ; Stumpp, Taiza ^[15] ; Antunes, Fernanda ^[16] ; Pereira, Gustavo Jose ^[16] ; Neerman-Arbez, Marguerite ^[3] ; Meloni, Vera Ayres ^[1] ; Drummond-Borg, Margaret ^[17] ; Melaragno, Maria Isabel ^[1] ; Reymond, Alexandre ^[2]

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^[1] Univ Fed Sao Paulo, Dept Morphol & Genet, Genet Div, Sao Paulo - Brazil

^[2] Univ Lausanne, Ctr Integrat Genom, Lausanne - Switzerland

^[3] Univ Geneva, Med Sch, Dept Genet Med & Dev, Geneva - Switzerland

^[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX - USA

^[5] CHU Lille, Hop Jeanne Flandre, Clin Genet, Lille - France

^[6] Univ Fed Sao Paulo, Psychobiol Dept, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Hosp Clin, Fac Med, Dept Pathol, Lab Citogen, LIM 03, Sao Paulo - Brazil

^[8] Univ Klinikum Jena, Inst Humangenet, Jena - Germany

^[9] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire - England

^[10] Univ Hosp Southampton, Genom Informat Grp, Southampton, Hants - England

^[11] Univ Hosp Southampton, Southampton Childrens Hosp, Southampton, Hants - England

^[12] Illumina Clin Serv Lab, San Diego, CA - USA

^[13] Med Coll Wisconsin, Dept Pediat, Sect Genet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 - USA

^[14] CHU Lille, Hop Jeanne Flandre, Inst Genet Med, Lille - France

^[15] Univ Fed Sao Paulo, Dev Biol Div, Sao Paulo - Brazil

^[16] Univ Fed Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[17] Cook Childrens Genet Clin, Ft Worth, TX - USA

• Tipo de documento: Artigo Científico
• Fonte: Human mutation; v. 39, n. 2, p. 281-291, FEB 2018.
• Citações Web of Science: 4

Resumo

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. (AU)

• Processo FAPESP: 14/11572-8 - Rearranjos cromossômicos e sua importância na etiologia das doenças genéticas: investigação citogenômica e molecular
• Beneficiário: Maria Isabel de Souza Aranha Melaragno
• Modalidade de apoio: Auxílio à Pesquisa - Temático