甲状腺激素转运体MCT8的突变会导致产前脑损伤和持续性髓鞘形成不足。
Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.
作者信息
López-Espíndola Daniela, Morales-Bastos Carmen, Grijota-Martínez Carmen, Liao Xiao-Hui, Lev Dorit, Sugo Ella, Verge Charles F, Refetoff Samuel, Bernal Juan, Guadaño-Ferraz Ana
机构信息
Instituto de Investigaciones Biomédicas Alberto Sols (D.L.-E., C.G.-M., J.B., A.G.-F.), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain; Carrera de Tecnología Médica (D.L.-E.), Facultad de Medicina, Universidad de Valparaíso, Alcalde Sergio Prieto Nieto 452, 2581907 Viña del Mar, Chile; Department of Pathology (C.M.-B.), La Paz University Hospital, E-28046 Madrid, Spain; Center for Biomedical Research on Rare Diseases (C.G-M., J.B.), Unit 708, E-28040 Madrid, Spain; Departments of Medicine (X.-H.L., S.R.), Pediatrics (S.R.), and Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Institute of Medical Genetics (D.L.), Wolfson Medical Center, Holon 58100, Israel; South Eastern Area Laboratory Services (E.S.), Prince of Wales Hospital, Randwick 2031, Australia; Sydney Children's Hospital (C.F.V.), Randwick, and School of Women's and Children's Health (C.F.V.), University of New South Wales, Sydney 2010, Australia.
出版信息
J Clin Endocrinol Metab. 2014 Dec;99(12):E2799-804. doi: 10.1210/jc.2014-2162.
CONTEXT
Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown.
OBJECTIVE
The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects.
DESIGN
We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy.
METHODS
Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed.
RESULTS
The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs.
CONCLUSIONS
The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.
背景
编码特定甲状腺激素转运蛋白的MCT8（SLC16A2）基因突变会导致一种X连锁疾病，伴有严重的精神运动发育迟缓、神经功能损害以及血清甲状腺激素水平异常。中枢神经系统损伤的本质尚不清楚。
目的
本研究的目的是通过分析MCT8缺陷患者的脑组织切片来明确该综合征的神经病理学特征。
设计
我们分析了一名孕30周男性胎儿和一名11岁男孩的脑切片，并分别以一名孕30周男性胎儿、一名孕28周男性胎儿、一名孕28周女性胎儿、一名10岁女孩和一名12岁男孩的脑组织作为对照。
方法
进行苏木精-伊红染色以及髓鞘碱性蛋白、70 kDa神经丝、小白蛋白、钙结合蛋白-D28k和突触素的免疫染色。还进行了甲状腺激素测定和脱碘酶的定量PCR。
结果
MCT8缺陷胎儿表现出皮质和小脑发育及髓鞘形成延迟，小白蛋白表达缺失，钙结合蛋白-D28k含量异常，轴突成熟受损，浦肯野细胞的生化分化减弱。11岁男孩表现出小脑结构改变、髓鞘形成不足、突触素和小白蛋白表达不足以及钙结合蛋白-D28k表达异常。MCT8缺陷胎儿的大脑皮质甲状腺激素减少50%，2型脱碘酶mRNA增加，3型脱碘酶mRNA减少。
结论
得出以下结论：1）MCT8缺陷导致的脑损伤是弥漫性的，无局灶性病变证据，且尽管出生时看似正常，但在胎儿期就已存在；2）髓鞘形成不足持续至11岁；3）这些发现与甲状腺激素向靶神经细胞转运受损导致发育中大脑甲状腺激素作用不足相符。
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