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The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe.
Eur J Hum Genet. 2002 Mar;10(3):197-203
Publication Type
Alessandra Maugeri
Kris Flothmann
Nadine Hemmrich
Sofie Ingvast
Paula Jorge
Eva Paloma
Reshma Patel
Jean-Michel Rozet
Jaana Tammur
Francesco Testa
Susana Balcells
Alan C Bird
Han G Brunner
Carel B Hoyng
Andres Metspalu
Francesca Simonelli
Rando Allikmets
Shomi S Bhattacharya
Michele D'Urso
Roser Gonzàlez-Duarte
Josseline Kaplan
Gerard J te Meerman
Rosário Santos
Marianne Schwartz
Guy Van Camp
Claes Wadelius
Bernhard H F Weber
Frans P M Cremers
Author Affiliation
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Eur J Hum Genet. 2002 Mar;10(3):197-203
Publication Type
ATP-Binding Cassette Transporters - genetics
Base Sequence
Gene Frequency
Molecular Sequence Data
Point Mutation
Research Support, Non-U.S. Gov't
United States
Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.
PubMed ID
11973624 View in PubMed
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Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark.
Eur J Hum Genet. 2016 Jul;24(7):1071-9
Publication Type
Galuh D N Astuti
Mette Bertelsen
Markus N Preising
Muhammad Ajmal
Birgit Lorenz
Sultana M H Faradz
Raheel Qamar
Rob W J Collin
Thomas Rosenberg
Frans P M Cremers
Eur J Hum Genet. 2016 Jul;24(7):1071-9
Publication Type
Leber Congenital Amaurosis - genetics - pathology
Mutation Rate
Mutation, Missense
RNA Splicing
cis-trans-Isomerases - genetics
Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in ~60?000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.
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PubMed ID
26626312 View in PubMed
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Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.
Am J Hum Genet. 2016 Sep 01;99(3):770-6
Publication Type
Konstantinos Nikopoulos
Pietro Farinelli
Basilio Giangreco
Chrysanthi Tsika
Beryl Royer-Bertrand
Martial K Mbefo
Nicola Bedoni
Ulrika Kjellström
Ikram El Zaoui
Silvio Alessandro Di Gioia
Sara Balzano
Katarina Cisarova
Andrea Messina
Sarah Decembrini
Sotiris Plainis
Styliani V Blazaki
Muhammad Imran Khan
Shazia Micheal
Karsten Boldt
Marius Ueffing
Alexandre P Moulin
Frans P M Cremers
Ronald Roepman
Yvan Arsenijevic
Miltiadis K Tsilimbaris
Sten Andréasson
Carlo Rivolta
Am J Hum Genet. 2016 Sep 01;99(3):770-6
Publication Type
Cell Cycle Proteins - genetics - metabolism
Cilia - pathology
Cohort Studies
Cone-Rod Dystrophies - complications - genetics - pathology - physiopathology
Exome - genetics
Eye - embryology - metabolism
Eye Proteins - metabolism
Fibroblasts - pathology
Hearing Loss, Sensorineural - complications - genetics - pathology - physiopathology
Introns - genetics
Middle Aged
Mutation - genetics
Protein Binding
RNA, Messenger - analysis
Usher Syndromes - pathology
Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(*)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.
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PubMed ID
27588451 View in PubMed
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