The rat Ruby (R) locus is Rab38:: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain
The rat Ruby (R) locus is Rab38:: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain
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DOI：
10.1007/s00335-004-2337-9
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发表时间：
2004-04-01
期刊：
影响因子：
2.5
通讯作者：
Spritz, RA
中科院分区：
文献类型：
--
作者：
Oiso, N;Riddle, SR;Spritz, RA
Hermansky-Pudlak综合征(HPS)是一组罕见的隐性疾病，由多个细胞质细胞器的生物发生缺陷导致眼皮肤白化、进行性肺纤维化、出血素质等异常。在人类中已知有7种不同的HPS基因；在老鼠中，至少有16个基因座与HPS样突变表型相关。在大鼠中，只有两个已知的HPS模型，Fawn-hooded(FH)和Tester Moriyama(TM)，这两个非互补菌株的HPS样色素减少和血小板储存池缺陷是由于染色体(Chr)上的Ruby(红眼稀释；R)基因座的突变引起的。我们已经确定R基因座是Rab38基因，确定大鼠R与小鼠巧克力(Cht)同源。此外，我们发现FH和TM大鼠具有相同的Rab38MetlIle突变，发生在相同的Chr I标记等位基因单倍型上，表明这两个菌株来自共同的祖先。这个祖先似乎是近交系Long Evans(LE)株的一个亚株，几个现代LE亚株在相同的Chr I标记单倍型上携带Rab38MetlIle R突变。这些发现对许多过去和正在进行的涉及FH和LE衍生鼠品系的研究具有重要意义。Hermansky-Pudlak综合征(HPS；MIM 203300)是一组常染色体隐性遗传病，其眼皮肤白化病、进行性和致死性肺纤维化以及由于血小板储存池不足而导致的出血素质是由于特定细胞质细胞器和颗粒：黑素体、溶酶体和血小板致密颗粒的生物发生缺陷所致(Spritz 1999,2000；Spritz et al.2003年)。在人类中，已知七种不同的HPS基因(oh等人)。1996年；Dell‘Angelica等人。1999年；Anikster等人。2001年；Suzuki et al.2002年；Li等人。2003年；Zhang et al.2003年)。在小鼠中，至少有16个与HPS样突变表型相关的基因座已知，其中7个与人类HPS基因座同源(Swank等人。1998；Bennett和Lamoreux 2003)。在老鼠身上，我们知道的要少得多。只有两个类似HPS的大鼠模型获得了成功。Description，Fawn-Hoded(FH；Tschopp and Zucker 1972)和Tester-Moriyama(TM；Hamada et al.1997年)，两者都表现出黄褐色的色素稀释和血小板储存池缺陷(图1)。FH和TM在双杂合子中不互补(Hamada等人)。1997)，表明这两株类似HPS的菌株在单个基因座上携带等位基因变异。FH一直是所有大鼠品系中研究最深入的之一，因为它也以肺动脉高压为特征(Kentera等人)。1988)、系统性高血压(Kuijpers And De Jong 1986)、进行性肾功能衰竭(Brown et al.1996年)，抑郁症(Rezvani et al.2002年)和酗酒(Rezvani等人2002年)。FH表型的色素减少和血小板储存池缺陷可归因于单一基因座Ruby(R)(La Vail 1981；Prieur and Meyers 1984)(也称为“红眼稀释”和“红眼黄色”；Hedrich 1990)的多向性效应，位于大鼠Chr 1(Castle and King 1949；Datta et al)上。2003年)，在其他导致肾脏疾病和高血压易感性的FH基因座附近，RF-1、RF-2和Bpfh-1(Brown等人)。1996年；Datta et al.2003年)。如图2所示，大鼠Chr1的这个区域与小鼠Chr7的一个区域处于保守的同步性片段，该区域包含三个与OCA和HPS相关的基因：Tyr(OCA Type1；OCA1)，Rab38(小鼠HPS模型巧克力；Loftus等人)。2002)和Vps33b(类似于用于小鼠HPS模型缓冲器的Vps33a；Suzuki等人。2003年)。这提示Rab38和Vps33b，以及不太可能的Tyr，可能是FH和TM大鼠R基因座的候选基因。FH和TM大鼠被认为有非常不同的起源(Tschopp和Zucker 1972；Hamada等人。因此，我们惊讶地在两个品系中发现了相同的Rab38基因突变，发生在相同的Chr 1微卫星标记等位基因的单倍型上，这表明FH和TM大鼠HPS模型株中的Rab38突变具有共同的祖先。我们在Long Evans(Long Evans)大鼠的几个亚系中发现了相同的Rab38突变和单倍型，历史分析表明FH和TM都有LE祖先。这些发现表明，FH/TM Rab38突变发生在祖先的LE亚株中，这对研究FH、TM和LE亚株的研究人员具有重要意义。
Hermansky-Pudlak syndrome (HPS) is a group of rare, recessive disorders in which oculocutaneous albinism, progressive pulmonary fibrosis, bleeding diathesis, and other abnormalities result from defective biogenesis of multiple cytoplasmic organelles. Seven different HPS genes are known in humans; in mouse, at least 16 loci are associated with HPS-like mutant phenotypes. in the rat, only two HPS models are known, Fawn-hooded (FH) and Tester Moriyama (TM), non-complementing strains in which HPS-like hypopigmentation and platelet storage pool deficiency result from a mutation of the Ruby (red eyed dilution; R) locus on Chromosome (Chr) 1. We have identified the R locus as the Rab38 gene, establishing that rat R is homologous to mouse chocolate (cht). Further, we show that FH and TM rats have identical Rab38 MetlIle mutations, occurring on an identical Chr I marker allele haplotype, indicating that these two strains derive from a common ancestor. This ancestor appears to have been a substrain of the outbred Long Evans (LE) strain, and several modem LE sub-strains carry the Rab38 MetlIle R mutation on the same Chr I marker haplotype. These findings have significant implications for the many past and ongoing studies that involve the FH and LE-derivative rat strains. Hermansky-Pudlak syndrome (HPS; MIM 203300) is a group of autosomal recessive diseases in which oculocutaneous albinism (OCA), progressive and fatal pulmonary fibrosis, and bleeding diathesis due to platelet storage pool deficiency result from defects in the biogenesis of specific cytoplasmic organelles and granules: melanosomes, lysosomes, and platelet dense granules (reviewed in Spritz 1999, 2000; Spritz et al. 2003). In humans, seven different HPS genes are known (Oh et al. 1996; Dell'Angelica et al. 1999; Anikster et al. 2001; Suzuki et al. 2002; Li et al. 2003; Zhang et al. 2003). In the mouse, at least 16 loci associated with HPS-like mutant phenotypes are known, seven of which are homologous to the human HPS loci (Swank et al. 1998; Bennett and Lamoreux 2003).In the rat, much less is known. Only two HPS-like rat models have been. described, Fawn-hooded (FH; Tschopp and Zucker 1972) and Tester-Moriyama (TM; Hamada et al. 1997), both of which exhibit fawn-hooded pigmentary dilution and platelet storage-pool deficiency (Fig. 1). FH and TM do not complement in double-heterozygotes (Hamada et al. 1997), indicating that these two HPS-like strains carry allelic variants at a single locus. FH has been one of the most intensively investigated of all rat strains, as it is also characterized by pulmonary hypertension (Kentera et al. 1988), systemic hypertension (Kuijpers and de Jong 1986), progressive renal failure (Brown et al. 1996), depression (Rezvani et al. 2002), and alcoholism (Rezvani et al. 2002). The hypopigmentation and platelet storage-pool deficiency aspects of the FH phenotype are attributable to pleiotropi effects of a single locus, Ruby (R) (La Vail 1981; Prieur and Meyers 1984) (also referred to as 'red-eyed dilution' and 'red-eyed yellow'; Hedrich 1990), located on rat Chr 1 (Castle and King 1949; Datta et al. 2003) in close proximity to other FH loci that contribute to renal disease and hypertension susceptibility, Rf-1, Rf-2, and Bpfh-1 (Brown et al. 1996; Datta et al. 2003). As shown in Fig. 2, this region of rat Chr 1 is in a segment of conserved synteny with a region of mouse Chr 7 that contains three genes related to OCA and HPS: Tyr (OCA type1; OCA1), Rab38 (mouse HPS model chocolate; Loftus et al. 2002), and Vps33b (similar to Vps33a for mouse HPS model buff; Suzuki et al. 2003). This suggested Rab38 and Vps33b, and less likely Tyr, as possible candidate genes for the R locus of FH and TM rats. FH and TM rats are considered to have very different origins (Tschopp and Zucker 1972; Hamada et al. 1997); therefore, we were surprised to find identical mutations of the Rab38 gene in both strains, occurring on identical haplotypes of Chr 1 microsatellite marker alleles, indicating that the Rab38 mutations in the FH and TM rat HPS-model strains share a common ancestor. We identified the same Rab38 mutation and haplotypes in several substrains of Long Evans (LE) rats, and historical analysis indicates that FH and TM both have LE ancestors. These findings indicate that the FH/TM Rab38 mutation arose in an ancestral LE sub-strain, raising significant implications for investigators working with FH, TM, and LE sub-strains.