Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.
Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.
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DOI：
10.1371/journal.pgen.1003646
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Bannasch DL
中科院分区：
文献类型：
--
作者：
Safra N;Bassuk AG;Ferguson PJ;Aguilar M;Coulson RL;Thomas N;Hitchens PL;Dickinson PJ;Vernau KM;Wolf ZT;Bannasch DL
神经管缺陷（NTD）是继发于神经管闭合或发育失败的中枢神经系统畸形的总称。所产生的病理可能涉及脑、脊髓和/或脊柱，以及相关的结构，如软组织或皮肤。据报道，这种情况是人类中较常见的出生缺陷之一，导致婴儿发病率和死亡率显着。其病因仍然知之甚少，但已知遗传、营养、环境因素或这些因素的组合在NTD的发展中起作用。与NTD相关的可变条件在犬中自然发生，并且先前在威玛犬品种中已有报道。利用犬种内的强联系不平衡，我们进行了全基因组关联分析，并绘制了一个基因组区域脊髓闭合不全，一个假定的NTD，使用4个受影响的和96个未受影响的威玛犬。犬8号染色体上的相关区域（pgenome = 3.0×10−5），经过100，000次排列后，编码18个基因，包括NKX 2 -8，一个在发育中的神经管中表达的同源框基因。 对受影响的威玛犬NKX 2 -8进行测序，发现该基因外显子2内存在G至AA移码突变，导致提前终止密码子，预计会产生截短蛋白。对脊柱裂患者NKX 2 -8的外显子进行测序，发现罕见变异（rs61755040和rs 10135525）明显过多（p = 0.036）。 这是NKX 2 -8在NTD病因学中的潜在作用的第一个文件，通过研究犬中自然发生突变的分子基础而成为可能。神经管缺陷（NTD）是由神经管闭合错误引起的出生缺陷，神经管是一种胚胎结构，在怀孕期间发育成中枢神经系统的组织。NTD通常会导致代价高昂的终身残疾。它们被认为是由营养，遗传和环境因素及其相互作用的组合引起的。然而，一个明显的机制目前尚不清楚。由于NTD的多因素性质，并且由于单个家庭中的多个病例很少，因此在人群中进行遗传研究变得困难。动物模型有助于剖析这种复杂性状的遗传学;然而，现有的啮齿动物模型并不能解释人类的所有NTD病例。狗是人类极好的生物医学模型，因为它们接受类似的医疗护理，分享我们的家庭环境，并发展与人类相似的自然发生的疾病。我们使用自然发生的NTD在威玛犬，称为脊髓闭合不全，以确定相关的调控基因，NKX 2 -8的突变。NKX 2 -8的突变随后在患有通常类似的称为脊柱裂的NTD的人类患者中被记录。这是第一个有记录的证据表明NKX 2 -8在NTD中发挥作用。预计这一发现将有助于我们理解导致NTD的机制。
Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome = 3.0×10−5), after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p = 0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs. Neural tube defects (NTDs) are birth defects resulting from errors in the closure of the neural tube, an embryonic structure which develops into tissues of the central nervous system during pregnancy. NTDs commonly lead to costly lifelong disabilities. They are considered to be caused by a combination of nutritional, inherited and environmental factors, and their interactions. However, an obvious mechanism is currently unknown. Genetic studies in human populations are made difficult by the multifactorial nature of NTDs and because multiple cases within a single family are rare. Animal models are helpful in dissecting the genetics of such complex traits; however existing rodent models do not explain all of the NTD cases in humans. Dogs are excellent biomedical models for humans since they receive comparable medical care, share our home environment, and develop naturally occurring diseases comparable to those in humans. We used a naturally occurring NTD in Weimaraner dogs, termed spinal dysraphism, to identify a mutation in an associated regulatory gene, NKX2-8. Mutations in NKX2-8 were subsequently documented in human patients with a generally similar NTD termed spina bifida. This is the first documented evidence that NKX2-8 has a role in NTDs. It is expected that this discovery will contribute to our understanding of the mechanisms leading to NTDs.
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影响因子：
5.4
作者：
Holland PW;Booth HA;Bruford EA
通讯作者：
Bruford EA
影响因子：
3.9
作者：
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Capra, Valeria
DOI：
10.1016/s0195-5616(92)50089-4
发表时间：
1992-07-01
影响因子：
1.9
作者：
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通讯作者：
MORGAN, JP
影响因子：
64.5
作者：
BALLING, R;DEUTSCH, U;GRUSS, P
通讯作者：
GRUSS, P
影响因子：
30.8
作者：
Karlsson, Elinor K.;Baranowska, Izabella;Lindblad-Toh, Kerstin
通讯作者：
Lindblad-Toh, Kerstin