An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Grasbeck syndrome in dogs
An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Grasbeck syndrome in dogs
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DOI：
10.1016/j.ymgme.2013.05.006
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发表时间：
2013-08-01
影响因子：
3.8
通讯作者：
Giger, Urs
中科院分区：
文献类型：
--
作者：
Fyfe, John C.;Hemker, Shelby L.;Giger, Urs
伴随选择性蛋白尿的钴胺素吸收不良是一种常染色体隐性遗传疾病，在人类中被称为伊默斯伦-格拉斯贝克综合征，之前在狗中也有过描述，原因是无羊膜 (AMN) 突变。由此产生的维生素 B-12 缺乏会导致幼年期造血障碍、嗜睡、发育迟缓以及危及生命的代谢紊乱。我们研究了 3 种患有钴胺素吸收不良的边境牧羊犬，并将受影响狗的疾病位点定位到犬 2 号染色体上的 2.9 Mb 纯合性区域。该区域包括 CUBN，编码 cubilin 的位点，cubilin 是一种外周膜蛋白，与 AMN 一起形成在回肠中表达的功能性内因子-钴胺素受体和肾近端小管中的多配体受体。分别通过放射性标记的钴胺素摄取研究和 SDS-PAGE 证明了钴胺素吸收不良和包含 CUBN 配体的蛋白尿。在受影响的狗的回肠和肾脏中，CUBN mRNA 和蛋白质表达分别减少了约 10 倍和约 20 倍。 DNA 测序表明，外显子 53 中的单碱基缺失预示着翻译移码和早期终止密码子可能引发无义介导的 mRNA 衰变。突变等位基因与边境牧羊犬亲属中的疾病分离。边境牧羊犬疾病表明，远离内因子钴胺素结合位点 C 端的 CUBN 突变可以消除受体表达并导致伊默斯伦-格拉斯贝克综合征。 (C) 2013 Elsevier Inc. 保留所有权利。
Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Grasbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B-12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9 Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced similar to 10 fold and similar to 20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Grasbeck syndrome. (C) 2013 Elsevier Inc. All rights reserved.