Open AccessNovel insights into the molecular pathogenesis of CYP 4V2 ‐associated Bietti's retinal dystrophy
Author(s) -
Astuti Galuh D. N.,
Sun Vincent,
Bauwens Miriam,
Zobor Ditta,
Leroy Bart P.,
Omar Amer,
Jurklies Bernhard,
Lopez Irma,
Ren Huanan,
Yazar Volkan,
Hamel Christian,
Kellner Ulrich,
Wissinger Bernd,
Kohl Susanne,
De Baere Elfride,
Collin Rob W. J.,
Koenekoop Robert K.
Publication year - 2015
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.109
Subject(s) - sanger sequencing , phenotype , gene , genetics , dystrophy , retinal , mutation , copy number variation , biology , microbiology and biotechnology , pathogenesis , medicine , pathology , ophthalmology , genome
Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2 . In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction ( qPCR ) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2 ‐negative patients with indistinguishable phenotypes from CYP4V2 ‐positive patients might suggest the presence of mutations outside the coding regions of CYP4V2 , or locus heterogeneity, which is unreported so far.