A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta.
A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta.
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DOI：
10.1371/journal.pgen.1000579
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发表时间：
2009-07
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：
Drögemüller C;Becker D;Brunner A;Haase B;Kircher P;Seeliger F;Fehr M;Baumann U;Lindblad-Toh K;Leeb T
成骨不全症（OI）是一种发生在人类和狗身上的遗传性疾病。它的特点是骨骼和牙齿极其脆弱。大多数人类和一些犬类成骨不全病例是由编码 I 型胶原亚基的 COL1A1 和 COL1A2 基因突变引起的。最近，发现 CRTAP 和 LEPRE1 基因突变可引起一些罕见形式的人类成骨不全症。许多成骨不全病例的致病突变尚未被发现。我们调查了患有常染色体隐性成骨不全症的腊肠犬。在 50 k 犬 SNP 芯片上仅对 5 只受影响的狗进行基因分型，使我们能够通过纯合性作图将致病突变定位到 21 号染色体上 5.82 Mb 的区间。对另外 5 个载体的单倍型分析将区间进一步缩小至 4.74 Mb。 SERPINH1 基因位于该区间内，编码参与胶原三螺旋正确折叠的重要伴侣。因此，我们认为 SERPINH1 是一个位置和功能候选基因，并对受影响和对照腊肠犬进行了突变分析。位于进化保守域的错义突变（c.977C>T，p.L326P）与OI表型完全相关。因此，我们已经确定了腊肠犬中 OI 的候选致病突变，并确定了第五个 OI 基因。成骨不全症（OI）是人类和狗的一种遗传性疾病，其特征是骨骼和牙齿极其脆弱。大多数人类成骨不全病例是由两种胶原蛋白基因之一的缺陷引起的。另外两个与胶原蛋白成熟相关的基因突变也可能导致某些患者出现成骨不全症。我们研究了患有成骨不全症的腊肠犬，并初步研究了成骨不全症中通常发生突变的两种已知胶原蛋白基因，但没有发现突变。随后，我们在五只受影响的腊肠犬的整个基因组中搜索了共享片段。该实验表明，腊肠犬成骨不全症的致病突变位于狗的 21 号染色体上。已知参与胶原蛋白成熟的 SERPINH1 基因位于该共享基因组区域。我们对健康和受影响的腊肠犬的 SERPINH1 基因进行了测序，发现所有受影响的狗都共有一个突变，但健康对照组则没有。因此，我们将 SERPINH1 确定为第五个 OI 基因，并且该基因内的突变是腊肠犬 OI 的最可能原因。了解这种突变可以进行基因测试，并使饲养者能够从腊肠犬繁殖群体中根除有害的等位基因。 SERPINH1 突变也可能导致某些人类 OI 形式，但尚未确定致病突变。
Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene. Osteogenesis imperfecta (OI) is a genetic condition of humans and dogs characterized by extremely fragile bones and teeth. Most human OI cases are caused by defects in one of two collagen genes. Mutations in two other genes related to collagen maturation can also lead to OI in some patients. We studied Dachshunds with OI and initially investigated the two known collagen genes that are normally mutated in OI but did not find a mutation. Subsequently, we performed a search for shared segments across the entire genome in five affected Dachshunds. This experiment revealed that the causative mutation for OI in Dachshunds is located on dog chromosome 21. The SERPINH1 gene known to be involved in collagen maturation is located in this shared genome region. We sequenced the SERPINH1 gene in healthy and affected Dachshunds and found a single mutation exclusively shared by all affected dogs but not by healthy controls. Thus we have identified SERPINH1 as a fifth OI gene and a mutation within this gene as the most likely cause of OI in Dachshunds. The knowledge of this mutation enables genetic testing and will allow breeders to eradicate the deleterious allele from the Dachshund breeding population. SERPINH1 mutations might also be responsible for some human OI forms, where the causative mutation has not yet been identified.
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DOI：
10.1073/pnas.0603676103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Wang, Hongyan;Parry, Samuel;Strauss, Jerome F., II
通讯作者：
Strauss, Jerome F., II
影响因子：
64.5
作者：
Morello, Roy;Bertin, Terry K.;Lee, Brendan
通讯作者：
Lee, Brendan
影响因子：
30.8
作者：
Cabral, Wayne A.;Chang, Weizhong;Marini, Joan C.
通讯作者：
Marini, Joan C.
影响因子：
4.8
作者：
Dementiev, A;Simonovic, M;Gettins, PGW
通讯作者：
Gettins, PGW
影响因子：
2.4
作者：
Seeliger, F;Leeb, T;Hewicker-Trautwein, M
通讯作者：
Hewicker-Trautwein, M