Abstract
EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers.
References
Feb 1, 1988·European Journal of Pediatrics·M Spranger, J Schapera
Apr 1, 1996·Clinical Dysmorphology·N M Roelfsema, J M Cobben
Oct 27, 1999·Cell·J CelliH van Bokhoven
Jun 7, 2000·American Journal of Human Genetics·P IanakievP Tsipouras
Jul 20, 2001·American Journal of Human Genetics·H van BokhovenH G Brunner
Jan 12, 2002·Prenatal Diagnosis·I WittersJ P Fryns
May 31, 2002·American Journal of Human Genetics·Hans van Bokhoven, Han G Brunner
Jun 28, 2002·American Journal of Human Genetics·Mary L MarazitaYou-e Liu
Apr 2, 2003·Human Molecular Genetics·Pascal H G DuijfHan G Brunner
Aug 25, 2004·Clinical Genetics·A K RayL L Field
Nov 13, 2004·Cell Cycle·Yi-Ping HuangEdward A Ratovitski
May 12, 2006·American Journal of Medical Genetics. Part a·Alison M Elliott, Jane A Evans
May 13, 2006·American Journal of Medical Genetics. Part a·Tuula RinneHan G Brunner
Jun 3, 2006·Journal of Medical Genetics·P LeoyklangV Shotelersuk
Jul 25, 2006·Cell Cycle·Mariangela RossiViola Calabrò
Jan 17, 2007·Cell Cycle·Tuula RinneHans van Bokhoven
Oct 5, 2007·Mutation Research·Tongxiu LuoXiushan Wu
Jun 3, 2008·Human Molecular Genetics·Sibel Aylin Ugur, Aslihan Tolun
Jul 24, 2008·PloS One·Teresa LopardoLuisa Guerrini
Apr 25, 2009·PloS One·Silvia PozziM Alessandra Vigano
Aug 12, 2009·Clinical and Experimental Dermatology·L SorasioM C Silengo
Nov 12, 2009·The British Journal of Dermatology·S E ClementsJ A McGrath
Apr 23, 2010·Journal of Dental Research·W YinZ Bian
Sep 3, 2010·PLoS Genetics·Evelyn N KouwenhovenHuiqing Zhou
Sep 22, 2010·Cell Cycle·A BellomariaSonia Melino
Sep 1, 2009·Indian Journal of Human Genetics·Geetanjali JindalVipul Kumar Gupta
Apr 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Chen ChenOsnat Herzberg
Apr 8, 2011·The Journal of Investigative Dermatology·Hans VanbokhovenWim Declercq
May 14, 2011·American Journal of Medical Genetics. Part a·Piranit N KantaputraWarissara Sripathomsawat
Jun 8, 2011·Journal of Dental Research·R A RomanoS Sinha
Aug 4, 2011·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics·Li DaiJun Zhu
Citations
Jun 6, 2013·International Journal of Colorectal Disease·Pengjun SuZhibo Zhang
Sep 12, 2014·Pediatric Dermatology·Jelena RumlHartmut Peters
Jun 29, 2015·European Journal of Medical Genetics·Emanuela PonziFiorella Gurrieri
Jun 16, 2015·PloS One·Wei YinZhuan Bian
Dec 19, 2017·Frontiers in Genetics·Baoheng GuiTaosheng Huang
Jun 29, 2016·American Journal of Medical Genetics. Part a·Annabelle EnriquezMeredith Wilson