Canine Generalized Progressive Retinal Atrophies-Clinical Manifestations and Recent Advances in Molecular Genetics

犬漸進性全面視網膜退化症－複雜臨床呈像及在分子遺傳學和致病基因之研究發現

林中天(Chung-Tien Lln)

《中華民國獸醫學會雜誌》 26卷2期 (2000/06) Pp. 84-95

https://doi.org/10.7009/JTCSVS.200006.0084

摘要

犬漸進位全面視網膜退化症（gPRA）為一類主要造成犬失明之遺傳性視網膜感光細胞疾病，發生在超過一百個犬種以上。在人類對等的疾病稱為色索性網膜炎（RP），為造成孩童及成人最主要的遺傳性失明原因。犬gPRA在各犬種之遺傳方式多為體染色體隱性遺傳（autosomal recessive），僅在西伯利亞哈士奇犬為X染色體性聯遺傳（X-linked inheritance）。造成犬gPRA之致病基因十分複雜，除了少數犬種以外，大多數gPRA之致病基因依不同犬種而不同。近年來多個歐美國家在gPRA分子遺傳學之各自研究努力，已發現兩個早發性gPRA亞型之致病基因：其中一型gPRA為發生在愛爾蘭雪達犬（Irish setter）之感光細胞發育不良第一型（rcd1）；另一型gPRA為威爾斯科基犬（Welsh corgi）之感光細胞發育不良第三型（rcd3）。此兩型gPRA病因之發現均由作者過去研究之劍橋大學小動物疾病分子遺傳實驗室分別於1993年及1999年發表。造成愛爾蘭雪達犬gPRA（rcd1）之致病基因為cGMP-phosphodiestase之beta單元（cGMP-PDEB）基因突變，而造成成爾斯柯基犬之gPRA（rcd3）致病基因為cGMP-phosphodiestase之alpha單元（cGMP-PDEA）基因突變。兩基因均為視網膜視覺傳導途徑（visual tansduction pathway）中之重要蛋白質基因。此兩基因亦廣泛地在其他許多犬種之gPRA中研究，並已排除其為其他至少二十個犬種gPRA之致病基因，顯示rcd1及rcd3和其他犬種之gPRA之致病基因不同（non-allelic），位於不同之染色體位置上。近十年來，利用功能性候選基因研究法（functional candidate gene approach）來深入研究許多動物及人類視網膜疾病之候選致病基因，特別是視網膜視覺傳導途徑中之蛋白質基因及感光細胞結構蛋白質基因，在gPRA所扮演之角色。這些研究發現已確定排除許多人類RP之致病基因為許多犬種gPRA之致病基因。至今在犬gPRA之病因研究，仍僅發現以上所述之兩個致病基因，顯見gPRA在不同犬種之分子遺傳學之複雜性及發現致病基因之困難。近五年在犬基因體圖（canine genome map）及基因鏈結圖（genetic linkage map）之發展，己可利用基因在犬染色體之位置來找尋候選致病基因（positional candidate gene approach），使找尋遺傳疾病之致病基因更有效率。以下之綜說為介紹犬gPRA在各犬種之複雜臨床呈像以及此病在分子遺傳學及致病基因之研究發現。

關鍵字

漸進性全面視網膜退化症 ； 視網膜發育異常 ； 遺傳性視網膜退化症 ； 遺傳性疾病 ； 犬

並列摘要

Canine generalized progressive retinal atrophy (gPRA or PRA) is a group of hereditary retinal photoreceptor diseases that is a leading cause of blindness in the dog. gPRA closely resembles retinitis pigmentosa (RP), the leading cause of inherited blindness in humans . Canine gPRA exhibits autosomal recessive and X-linked modes of inheritance. but the recessive form of gPRA is the more common condition. Progress in molecular genetics has allowed the identification of the gene mutations responsible for two early-onset subtypes of gPRA, namely rod-cone dysplasia type one (rcd 1) in the Irish setter in 1993, and recently rod-cone dysplasia type three (rcd3) in the Cardigan Welsh corgi in 1999, respectively. The gene mutation causing rcd1 is the beta subunit of cyclic guanosine monophosphate phosphodiesterase (cGMP-PDEB) while the mutation of alpha subunit of cGMP (PDEA) causes rcd3. Both genes encode distinct subunits of the cGMP-PDE protein involved in the visual transduction pathway. Investigation of these genes in other dog breeds with gPRA has excluded these genes as the causes of gPRA in those breeds suggesting that the causal gene loci in those breeds are not allelic to the rcd 1 or rcd3. By means of functional candidate gene approach, other retinal genes have been intensively investigated, particularly those genes encoding proteins in the visual transduction pathway and photoreceptor structural proteins in the retina. However, most gene defects causing gPRA in the dog are still unknown. Recent development in the mapping of the canine genome has produced more markers on chromosomes to allow mapping of gPRA genes and positional candidate gene approach. This article will review research advances aimed to characterize subtypes of gPRA and understand the causes of gPRA in the dog.

並列關鍵字

gPRA ； Retinal dystrophies ； Hereditary retinal degeneration ； Inherited diseases ； Dog