A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats
A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats
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DOI：
10.1016/j.ymgme.2006.12.003
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发表时间：
2007-04-01
影响因子：
3.8
通讯作者：
Henthorn, Paula S.
中科院分区：
文献类型：
--
作者：
Fyfe, John C.;Kurzhals, Rebeccah L.;Henthorn, Paula S.
糖原分支酶（GBE）活性缺乏导致糖原储存病IV型（GSD IV），这是一种常染色体隐性代谢错误。异常糖原在肌细胞、肝细胞和神经元中积累，引起不同程度的进行性、良性到致命的器官功能障碍。先前在挪威森林猫（NFC）中描述了一种自然发生的人类GSD IV同源物。在这里，我们报告说，虽然大多数受影响的小猫在出生时或出生后不久死亡，可能是由于低血糖，围产期的幸存者在临床上表现正常，直到5个月大时出现进行性神经肌肉变性。对受感染猫的分子调查显示，肝脏和肌肉中GBE1 mRNA产物剪接异常，缺乏GBE交叉反应物质。受影响的猫是纯合子，在GBE1中基因组DNA的复杂重排，由6.2kb的缺失位点插入334 bp组成，从内含子11延伸到内含子12 (g.v ivs11 +1552(-)IVS12-1339 de16.2kb ins334 bp)，去除外显子12。一项基于pcr的等位基因特异性测试表明，这种重排与GSD IV亲缘猫的疾病分离，而在无亲缘关系的正常猫中没有发现。对402只私人拥有的NFC进行筛查，发现58只携带携带者和4只受影响的猫。研究猫GSD IV的分子特征将有助于进一步研究GSD IV的病理生理和开发这种独特动物模型的新疗法。(c) 2006爱思唯尔公司版权所有。
Deficiency of glycogen branching enzyme (GBE) activity causes glycogen storage disease type IV (GSD IV), an autosomal recessive error of metabolism. Abnormal glycogen accumulates in myocytes, hepatocytes, and neurons, causing variably progressive, benign to lethal organ dysfunctions. A naturally occurring orthologue of human GSD IV was described previously in Norwegian forest cats (NFC). Here, we report that while most affected kittens die at or soon after birth, presumably due to hypoglycemia, survivors of the perinatal period appear clinically normal until onset of progressive neuromuscular degeneration at 5 months of age. Molecular investigation of affected cats revealed abnormally spliced GBE1 mRNA products and lack of GBE cross-reactive material in liver and muscle. Affected cats are homozygous for a complex rearrangement of genomic DNA in GBE1, constituted by a 334 bp insertion at the site of a 6.2kb deletion that extends from intron 11 to intron 12 (g.IVS11+1552(-)IVS12-1339 de16.2kb ins334 bp), removing exon 12. An allele-specific, PCR-based test demonstrates that the rearrangement segregates with the disease in the GSD IV kindred and is not found in unrelated normal cats. Screening of 402 privately owned NFC revealed 58 carriers and 4 affected cats. The molecular characterization of feline GSD IV will enhance further studies of GSD IV pathophysiology and development of novel therapies in this unique animal model. (c) 2006 Elsevier Inc. All rights reserved.