Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses.
Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses.
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DOI：
10.1371/journal.pgen.1002653
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Leeb T
中科院分区：
文献类型：
--
作者：
Hauswirth R;Haase B;Blatter M;Brooks SA;Burger D;Drögemüller C;Gerber V;Henke D;Janda J;Jude R;Magdesian KG;Matthews JM;Poncet PA;Svansson V;Tozaki T;Wilkinson-White L;Penedo MC;Rieder S;Leeb T
在胎儿发育过程中，神经嵴来源的成黑素细胞迁移到整个身体表面并分化成黑素细胞，即产生色素的细胞。在这个精确调节的过程中的改变可以导致白色斑点图案。马的白色斑点模式是一种复杂的性状，具有很大的表型变异，范围从最小的白色斑点到完全白色马。“溅白色”模式的主要特征是一个非常大的火焰，往往伴随着延长白色标记在远端四肢和蓝色的眼睛。一些，但不是所有的，溅白色马是聋子。我们分析了一个季度马家庭分离的飞溅的白色外套的颜色。对31匹马进行的全基因组连锁分析显示，6号染色体上含有PAX 3基因的区域的阳性LOD评分为1.6。然而，连锁数据不符合单基因遗传的一个单一的完全外显突变。我们对PAX 3基因进行了测序，并在一些（但不是全部）飞溅白色夸特马中发现了一个错义突变。全基因组关联分析表明MITF附近存在潜在的第二个信号。因此，我们对MITF基因进行了测序，并在黑素细胞特异性启动子中发现了10 bp的插入。MITF启动子变体存在于来自所研究家族的一些飞溅白色夸特马中，但也存在于来自其他马品种的飞溅白色马中。最后，我们确定了两个额外的非同义突变的MITF基因在无关的马与白色斑点表型。因此，MITF和PAX 3中的几个独立突变以及EDNRB和KIT基因中的已知变体解释了大部分马具有更极端的白色斑点表型。白色斑点毛色表型是黑素细胞发育异常的结果。因此，对具有遗传性白色斑点表型的家畜的分析有助于更好地理解控制色素产生细胞的增殖、迁移、分化和存活的复杂遗传网络。我们分析了马的所谓的斑点白色表型，其特征是非常独特的大火焰，腿上延伸的白色斑纹和蓝色眼睛。溅过水的白色马通常也是聋子。然而，表型变化很大，在一些表达最少的马中，不能明确区分斑点白色表型与“常见”白色斑纹。我们研究了不同品种的马，发现PAX 3基因中的一个突变和MITF基因中的两个突变导致了斑点白色表型。我们在一匹Franches-Montagnes马中发现的MITF基因的第三个突变导致了一种新的毛色表型，称为macchiato。人类中的类似突变会导致Waardenburg或Tietz综合征，这两种综合征的特征都是色素沉着缺陷和耳聋倾向。我们的研究揭示了一个显着比例的白色斑点表型之间的完全无色素的马和常见的白色标记的中间的分子基础。
During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes. White spotting coat color phenotypes are the result of aberrations in the development of melanocytes. The analysis of domestic animals with heritable white spotting phenotypes thus helps to better understand the complicated genetic network controlling the proliferation, migration, differentiation, and survival of pigment producing cells. We analyzed the so-called splashed white phenotype in horses, which is characterized by a very distinctive large blaze, extended white markings on the legs, and blue eyes. Splashed white horses are also frequently deaf. However, the phenotype is quite variable and, in some horses with minimal expression, the splashed white phenotype cannot be unambiguously discriminated from the “common” white markings. We studied horses from various breeds and found one mutation in the PAX3 gene and two mutations in the MITF gene that cause the splashed white phenotype. A third mutation in the MITF gene, which we found in a single Franches-Montagnes horse, causes a new coat color phenotype, termed macchiato. Similar mutations in humans cause either Waardenburg or Tietz syndrome, which both are characterized by pigmentation defects and a predisposition for deafness. Our study reveals the molecular basis for a significant proportion of white spotting phenotypes that are intermediate between completely unpigmented horses and common white markings.
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影响因子：
4.5
作者：
Silver DL;Hou L;Somerville R;Young ME;Apte SS;Pavan WJ
通讯作者：
Pavan WJ
影响因子：
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作者：
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Leeb T
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通讯作者：
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