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2015 ; 11
(12
): e1005723
Nephropedia Template TP
Vollrath D
; Yasumura D
; Benchorin G
; Matthes MT
; Feng W
; Nguyen NM
; Sedano CD
; Calton MA
; LaVail MM
PLoS Genet
2015[Dec]; 11
(12
): e1005723
PMID26656104
show ga
Inherited photoreceptor degenerations (IPDs) are the most genetically
heterogeneous of Mendelian diseases. Many IPDs exhibit substantial phenotypic
variability, but the basis is usually unknown. Mutations in MERTK cause recessive
IPD phenotypes associated with the RP38 locus. We have identified a murine
genetic modifier of Mertk-associated photoreceptor degeneration, the C57BL/6 (B6)
allele of which acts as a suppressor. Photoreceptors degenerate rapidly in
Mertk-deficient animals homozygous for the 129P2/Ola (129) modifier allele,
whereas animals heterozygous for B6 and 129 modifier alleles exhibit an unusual
intermixing of degenerating and preserved retinal regions, with females more
severely affected than males. Mertk-deficient mice homozygous for the B6 modifier
allele display degeneration only in the far periphery, even at 8 months of age,
and have improved retinal function compared to animals homozygous for the 129
allele. We genetically mapped the modifier to an approximately 2-megabase
critical interval that includes Tyro3, a paralog of Mertk. Tyro3 expression in
the outer retina varies with modifier genotype in a manner characteristic of a
cis-acting expression quantitative trait locus (eQTL), with the B6 allele
conferring an approximately three-fold higher expression level. Loss of Tyro3
function accelerates the pace of photoreceptor degeneration in Mertk knockout
mice, and TYRO3 protein is more abundant in the retinal pigment epithelium (RPE)
adjacent to preserved central retinal regions of Mertk knockout mice homozygous
for the B6 modifier allele. Endogenous human TYRO3 protein co-localizes with
nascent photoreceptor outer segment (POS) phagosomes in a primary RPE cell
culture assay, and expression of murine Tyro3 in cultured cells stimulates
phagocytic ingestion of POS. Our findings demonstrate that Tyro3 gene dosage
modulates Mertk-associated retinal degeneration, provide strong evidence for a
direct role for TYRO3 in RPE phagocytosis, and suggest that an eQTL can modify a
recessive IPD.
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