Original articleClinical phenotypes in carriers of Leber congenital amaurosis mutations
Section snippets
Patients and methods
Informed consent was obtained from all carriers or their legal guardians in accordance with the Declaration of Helsinki. The Institutional Review Board at the University of Illinois Medical Center approved this project. Two of the authors (JAG, GAF) examined 30 carriers from families with various LCA genotypes for both fundus and ERG abnormalities.
Electroretinograms were obtained by either of 2 procedures previously described.14, 15 All ERGs were performed according to International Society for
Results
Classical genetic teaching dictates that recessive mutations cause a phenotype in the affected patient, because both copies of the defective gene are present, but not in the carrier parents and/or children, who carry only 1 copy of the defective allele and are presumably protected by the wild-type allele. Nevertheless, in our cohort, we found that 22 of the 30 LCA carriers (73.3%) had a phenotype determined from detailed ERG measurements and/or careful retinal examination.
Thirty carriers, 17
Discussion
A limited number of reports have previously observed fundus and/or ERG abnormalities in LCA carriers associated with mutations in the AIPL122 (Invest Ophthalmol Vis Sci 45:5109, 2004), GUCY2D,18 RPE6523, 24 (Invest Ophthalmol Vis Sci 41[suppl]:4, 2000), and the RPGRIP1 genes (Invest Ophthalmol Vis Sci 45:4728, 2004). As in previous reports, we observed a spectrum of clinical phenotypic expression in our cohort of 30 LCA carriers representing 5 different LCA genotypes. To date, reported
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2018, Developmental BiologyCitation Excerpt :Interestingly, mutations in RPGRIP1L and RPGRIP1 result in different mouse and human ciliopathies (Tables S1, S2 and S3). RPGRIP1 mutations lead to eye defects in mice and humans (Abouzeid et al., 2016; Booij et al., 2005; Chen et al., 2013; Coppieters et al., 2014; Dryja et al., 2001; Fakhratova, 2013; Fernández-Martínez et al., 2011; Galvin et al., 2005; Gerber et al., 2001; Hameed et al., 2003; Han et al., 2017; Hanein et al., 2004; Huang et al., 2017, 2016, 2013; Imani et al., 2018; Kikuchi et al., 2015; Li et al., 2011, 2009; McKibbin et al., 2010; Neveling et al., 2013; Roepman et al., 2005; Sanchez-Navarro et al., 2018; Saqib et al., 2015; Seong et al., 2008; Suzuki et al., 2014; Tiwari et al., 2016; Vallespin et al., 2007; Verma et al., 2013; Walia et al., 2010; Wang et al., 2016, 2013; Won et al., 2009; Zernant et al., 2005; Zhao et al., 2003), RPGRIP1L mutations affect the development of the brain, the eyes, the lung, the heart, the kidneys, the liver, the limbs, and the skin (Alazami et al., 2012; Arts et al., 2007; Besse et al., 2011; Brancati et al., 2008; Chen et al., 2015; Delous et al., 2007; Doherty et al., 2010; Fahim et al., 2011; Gerhardt et al., 2013; Halbritter et al., 2012; Khanna et al., 2009; Laclef et al., 2015; Otto et al., 2011; Stratigopoulos et al., 2014; Summers et al., 2017; Szymanska et al., 2012; Vierkotten et al., 2007; Wolf et al., 2007). Patients bearing mutations in RPGRIP1 suffer from Retinitis Pigmentosa (RP), Cone Rod Dystrophy (CRD), Inherited Retinal Dystrophy (IRD) and Leber’s Congenital Amaurosis (LCA) (Abouzeid et al., 2016; Booij et al., 2005; Chen et al., 2013; Coppieters et al., 2014; Dryja et al., 2001; Fakhratova, 2013; Fernández-Martínez et al., 2011; Galvin et al., 2005; Gerber et al., 2001; Hameed et al., 2003; Han et al., 2017; Hanein et al., 2004; Huang et al., 2017, 2016, 2013; Imani et al., 2018; Kikuchi et al., 2015; Li et al., 2011, 2009; McKibbin et al., 2010; Neveling et al., 2013; Roepman et al., 2005; Sanchez-Navarro et al., 2018; Saqib et al., 2015; Seong et al., 2008; Suzuki et al., 2014; Tiwari et al., 2016; Vallespin et al., 2007; Verma et al., 2013; Walia et al., 2010; Wang et al., 2016, 2013; Zernant et al., 2005), while patients with mutations in RPGRIP1L suffer from Meckel syndrome (MKS), Joubert syndrome (JBTS), Cerebellar Vermis Aplasia Oligophrenia Congenital Ataxia Coloboma Hepatic Fibrosis (COACH), Nephronophtisis (NPHP), Bardet-Biedl syndrome (BBS), Retinitis Pigmentosa (RP) and Leber’s Congenital Amaurosis (LCA) (Alazami et al., 2012; Arts et al., 2007; Brancati et al., 2008; Chaki et al., 2011; Delous et al., 2007; Doherty et al., 2010; Fahim et al., 2011; Halbritter et al., 2012; Khanna et al., 2009; Otto et al., 2011; Summers et al., 2017; Szymanska et al., 2012; Wolf et al., 2007).
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2018, Progress in Retinal and Eye ResearchCitation Excerpt :An interesting question regarding the effect of GUCY2D mutation on retinal function is whether individuals who carry heterozygous recessive mutations develop any mild signs of retinal disease. Aiming to answer this question, clinical analysis of parents of LCA1 patients has been reported (Galvin et al., 2005; Koenekoop et al., 2002), with a total of four parents who are heterozygous for identified GUCY2D mutations (ages 40–55 years). Some of the patients reported mild and recent visual impairment (including difficulties driving at night and photoaversion during the day) with best-corrected visual acuity that was normal or subnormal and with normal appearance of the retina.
Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands
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2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
Manuscript no. 240288.
Supported in part by a center grant from The Foundation Fighting Blindness, Owings Mills, Maryland (GAF, EMS); The Grant Healthcare Foundation, Chicago, Illinois; an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, New York; and Foundation Fighting Blindness Canada, Toronto, Canada, and FRSQ Canada, Montreal, Canada (RKK).