Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish.
Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish.
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DOI：
10.1002/humu.24162
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发表时间：
2021-04
期刊：
影响因子：
3.9
通讯作者：
Hadley Miller N
中科院分区：
文献类型：
--
作者：
Terhune EA;Cuevas MT;Monley AM;Wethey CI;Chen X;Cattell MV;Bayrak MN;Bland MR;Sutphin B;Trahan GD;Taylor MRG;Niswander LA;Jones KL;Baschal EE;Antunes L;Dobbs M;Gurnett C;Appel B;Gray R;Hadley Miller N
特发性脊柱侧凸（IS）是一种脊柱疾病，影响高达3%的健康儿童。IS具有很强的家族遗传成分，并且由于表型和遗传性的显著变异性而被认为是遗传复杂的。先前的研究确定了可能导致IS易感性的假定位点和变体，包括ECM、纤毛和肌动蛋白网络，但遗传结构和潜在机制仍未解决。在这里，我们使用了来自一个多代IS家族中三个受影响个体的全外显子组测序，并鉴定了19种不常见的变异（MAF <0.05）。对其他家族成员的基因分型鉴定出纤毛基因KIF 7内的候选杂合变体（H1115 Q，G>C，rs 142032413），KIF 7是刺猬（Hh）信号通路内的调节因子。对第二组不相关的IS个体和对照进行重测序，仅在受影响的个体中发现了KIF 7的几个严重突变。随后，我们使用CRISPR-Cas9生成了kif 7的突变斑马鱼模型。kif 7 co 63/co 63斑马鱼表现出严重的脊柱侧凸，出现在幼年期，并逐渐发展到成年期。我们没有观察到畸形的大脑，Reissner纤维，或中央管纤毛在kif 7 co 63/co 63胚胎，虽然改变Hh通路基因表达。这项研究表明，KIF 7依赖性Hh信号传导的缺陷可能会导致IS患者的发病机制。
Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within ECM, cilia and actin networks, but the genetic architecture and underlying mechanisms remains unresolved. Here, we used whole exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (MAF <0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of a second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This research suggests defects in KIF7-dependent Hh signaling may drive pathogenesis in a subset of individuals with IS.
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影响因子：
10.5
作者：
Chong YC;Mann RK;Zhao C;Kato M;Beachy PA
通讯作者：
Beachy PA
特发性脊柱侧弯的斑马鱼模型将脑脊液流缺陷与脊柱曲率联系起来。
DOI：
10.1126/science.aaf6419
发表时间：
2016-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Grimes DT;Boswell CW;Morante NF;Henkelman RM;Burdine RD;Ciruna B
通讯作者：
Ciruna B
DOI：
10.1186/1748-7161-1-2
发表时间：
2006-03-31
期刊：
Scoliosis
影响因子：
--
作者：
Asher MA;Burton DC
通讯作者：
Burton DC
影响因子：
3.7
作者：
Einarsdottir E;Grauers A;Wang J;Jiao H;Escher SA;Danielsson A;Simony A;Andersen M;Christensen SB;Åkesson K;Kou I;Khanshour AM;Ohlin A;Wise C;Ikegawa S;Kere J;Gerdhem P
通讯作者：
Gerdhem P
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.