PMID- 30820151
OWN - NLM
STAT- MEDLINE
DCOM- 20190614
LR  - 20221207
IS  - 1090-0535 (Electronic)
IS  - 1090-0535 (Linking)
VI  - 25
DP  - 2019
TI  - A novel intronic mutation of PDE6B is a major cause of autosomal recessive 
      retinitis pigmentosa among Caucasus Jews.
PG  - 155-164
AB  - PURPOSE: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort 
      of Jewish patients from Caucasia. METHODS: Patients underwent a detailed 
      ophthalmic evaluation, including funduscopic examination, visual field testing, 
      optical coherence tomography (OCT), and electrophysiological tests, 
      electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis 
      was performed with a combination of whole exome sequencing (WES) and Sanger 
      sequencing. Bioinformatic analysis of the WES results was performed via a 
      customized pipeline. Pathogenicity of the identified intronic variant was 
      evaluated in silico using the web tool Human Splicing Finder, and in vitro, using 
      a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to 
      demonstrate a founder effect, and the decay of LD over generations around the 
      mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the 
      most recent common ancestor. RESULTS: In eight patients with RP from six 
      unrelated families, all of Caucasus Jewish ancestry, we identified a novel 
      homozygous intronic variant, located at position -9 of PDE6B intron 15. The 
      c.1921-9C>G variant was predicted to generate a novel acceptor splice site, nine 
      bases upstream of the original splice site of intron 15. In vitro splicing assay 
      demonstrated that this novel acceptor splice site is used instead of the 
      wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to 
      cause a frameshift. The presence of a common ancestral haplotype in 
      mutation-bearing chromosomes was compatible with a founder effect. CONCLUSIONS: 
      The PDE6B c.1921-9C>G intronic mutation is a founder mutation that accounts for 
      at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This 
      result is highly important for molecular diagnosis, carrier screening, and 
      genetic counseling in this population.
FAU - Tatour, Yasmin
AU  - Tatour Y
AD  - Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
      Technology, Haifa, Israel.
FAU - Tamaiev, Jonathan
AU  - Tamaiev J
AD  - Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
      Technology, Haifa, Israel.
FAU - Shamaly, Shamaly
AU  - Shamaly S
AD  - Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel.
FAU - Colombo, Roberto
AU  - Colombo R
AD  - Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of 
      the Sacred Heart, Milan, Italy.
AD  - Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda 
      Metropolitan Hospital, Milan, Italy.
FAU - Bril, Ephrat
AU  - Bril E
AD  - Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 
      Jerusalem, Israel.
FAU - Rabinowitz, Tom
AU  - Rabinowitz T
AD  - Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Yaakobi, Alona
AU  - Yaakobi A
AD  - Department of Ophthalmology, Hillel Yaffe Medical Center, Hadera, Israel.
FAU - Mezer, Eedy
AU  - Mezer E
AD  - Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
      Technology, Haifa, Israel.
AD  - Alberto Moscona Department of Ophthalmology, Rambam Health Care Center, Haifa, 
      Israel.
FAU - Leibu, Rina
AU  - Leibu R
AD  - Alberto Moscona Department of Ophthalmology, Rambam Health Care Center, Haifa, 
      Israel.
FAU - Tiosano, Beatrice
AU  - Tiosano B
AD  - Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
      Technology, Haifa, Israel.
AD  - Department of Ophthalmology, Hillel Yaffe Medical Center, Hadera, Israel.
FAU - Shomron, Noam
AU  - Shomron N
AD  - Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Chowers, Itay
AU  - Chowers I
AD  - Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 
      Jerusalem, Israel.
FAU - Banin, Eyal
AU  - Banin E
AD  - Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 
      Jerusalem, Israel.
FAU - Sharon, Dror
AU  - Sharon D
AD  - Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 
      Jerusalem, Israel.
FAU - Ben-Yosef, Tamar
AU  - Ben-Yosef T
AD  - Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
      Technology, Haifa, Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190222
PL  - United States
TA  - Mol Vis
JT  - Molecular vision
JID - 9605351
RN  - 0 (RNA Splice Sites)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6)
RN  - EC 3.1.4.35 (PDE6B protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Computational Biology
MH  - Cyclic Nucleotide Phosphodiesterases, Type 6/deficiency/*genetics
MH  - Electroretinography
MH  - Evoked Potentials, Visual/physiology
MH  - Exons
MH  - Female
MH  - Founder Effect
MH  - *Frameshift Mutation
MH  - Gene Expression
MH  - Genes, Recessive
MH  - Homozygote
MH  - Humans
MH  - Introns
MH  - *Jews
MH  - Linkage Disequilibrium
MH  - Male
MH  - Middle Aged
MH  - *RNA Splice Sites
MH  - Retina/diagnostic imaging/metabolism/pathology
MH  - Retinitis Pigmentosa/diagnostic imaging/ethnology/*genetics/pathology
MH  - Siberia/ethnology
MH  - Tomography, Optical Coherence
MH  - Exome Sequencing
PMC - PMC6386512
EDAT- 2019/03/02 06:00
MHDA- 2019/06/15 06:00
PMCR- 2019/01/01
CRDT- 2019/03/02 06:00
PHST- 2018/10/14 00:00 [received]
PHST- 2019/02/20 00:00 [accepted]
PHST- 2019/03/02 06:00 [entrez]
PHST- 2019/03/02 06:00 [pubmed]
PHST- 2019/06/15 06:00 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 15 [pii]
PST - epublish
SO  - Mol Vis. 2019 Feb 22;25:155-164. eCollection 2019.