AUTOSOMAL RECESSIVE RETINITIS PIGMENTOSA DUE TO ABCA4 MUTATIONS CLINICAL,
Invest Ophthalmol Vis Sci. 2012 Mar 6. [Epub ahead of print]
Mullins RF, Kuehn MH, Radu RA, Enriquez GS, East JS, Schindler EI, Travis GH, Stone EM. Department of Ophthalmology and Visual Sciences, University of Iowa, 375 Newton Rd, Iowa City, Iowa, 52242, United States.
Purpose: Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous condition characterized by progressive loss of retinal photoreceptor cells. In order to gain new insights into the pathogenesis of ARRP we evaluated the morphological, biochemical, and gene expression changes in eyes from a human donor with ARRP due to mutations in the ABCA4 gene.Methods: Eyes were obtained post-mortem from a donor with end-stage retinitis pigmentosa. The coding sequences of the RDS, RHO and ABCA4 genes were screened for disease causing mutations. Morphological changes in different regions of the retina were examined histologically and levels of lipofuscin-associated bisretinoids were measured. Gene expression was examined in retinal/choroidal tissue using microarray analysis, and all parameters were compared to those in unaffected control donors.
Results: Genetic analysis of t he donor`s DNA identified 2 mutations in the ABCA4 gene IVS14+1G>C and Phe1440del1 cT, each on a separate allele. Morphological evaluation revealed complete loss of the outer nuclear layer, remodeling of the inner retina, loss of retinal vasculature, and regional neovascularization. The RPE and choriocapillaris exhibited regional preservation. Microarray analysis revealed loss of photoreceptor cell-associated transcripts, with preservation of multiple genes expressed specifically in inner retinal neurons.
Conclusions: The persistence of transcripts expressed by inner retinal neurons suggests that, in spite of the significant plasticity that occurs during retinal degeneration, bipolar cells and ganglion cells remain at least partially differentiated. This study suggests that some forms of therapy currently under investigation may have benefit even in advanced retinal degeneration.
PMID: 22395892 [PubMed - as supplied by publisher] 中文簡述： 目的：常染色體隱性遺傳視網膜色素病變（ARRP）是一種遺傳異質性的表現，其特點是視網膜感光細胞逐漸喪失。為了獲得新的見解，我們評估的形態，其生化和基因表達在眼睛的變化，從這位患有視網膜色素病變ARRP捐贈者身上，ABCA4 gene.Methods基因發病，致病突變的RDS，rho和ABCA4基因的編碼序列進行了篩選。在不同區塊的視網膜形態學變化，進行了對組織學和脂褐素相關bisretinoids水平測量的檢查。在視網膜/脈絡膜組織，藉由基因芯片分析基因表達的研究中，所有的參數進行了比較不受影響控制者。
成果：捐贈者的DNA鑑定ABCA4基因IVS14+1 G C和Phe1440del1 CT，每一個單獨的等位基因突變的遺傳分析。形態學評估顯示，其外核層將完全喪失，內層視網膜的改造將喪失視網膜血管和區域的新生血管。基因芯片分析發現感光細胞相關轉錄的損失，視網膜色素上皮細胞和脈絡膜區域，與多個基因的視網膜神經細胞都得以保存。