A New PAX8 Mutation Causing Congenital Hypothyroidism in Three Generations of a Family Is Associated with Abnormalities in the Urogenital Tract
A New PAX8 Mutation Causing Congenital Hypothyroidism in Three Generations of a Family Is Associated with Abnormalities in the Urogenital Tract
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DOI：
10.1089/thy.2012.0649
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发表时间：
2013-09-01
期刊：
影响因子：
6.6
通讯作者：
Pohlenz, Joachim
中科院分区：
文献类型：
--
作者：
Carvalho, Ana;Hermanns, Pia;Pohlenz, Joachim
背景：虽然甲状腺发育不良是先天性甲状腺功能减退症（CH）最常见的原因，但其分子基础仍然难以捉摸。事实上，只有少数甲状腺发育不良的病例（2%-3%）可以确定潜在的遗传缺陷。本研究的目的是筛选PAX8基因和PAX2基因在一个家族6例CH跨越三代，并表现为泌尿生殖器畸形。在这里，我们报告了一个病例系列和PAX8基因突变的体外表征。方法：在三级保健转诊中心进行调查。指标病例在7个月大时被诊断为先天性甲状腺功能减退，当时他表现出严重的哺乳障碍、便秘和发育不良。左旋甲状腺素治疗可纠正症状，并伴有追赶性生长。他的后代，包括两个儿子、一个女儿和两个孙女，都受到CH的影响，其中三个在新生儿筛查时被诊断为CH。超声显示正常位置的甲状腺体积缩小。6名受影响的家庭成员中有5人（包括第一例）患有泌尿生殖系统畸形，包括不完全马蹄肾、睾丸隐睾、鞘膜积液和输尿管膨出。6例患者中有3例出现斜视。未发现其他躯体畸形。结果：PAX8基因的直接测序结果显示，在所有受影响的个体中都有一个新的杂合突变（c.74C . >G）。这种突变导致脯氨酸在密码子25 （P25R）上被精氨酸取代。荧光显微镜显示P25R通常位于细胞核内。在瞬时转染研究中，当使用在甲状腺球蛋白启动子控制下的荧光素酶报告基因构建时，这种突变导致转录激活能力降低。这种降低的转激活能力是由于DNA结合能力的丧失，如电泳迁移率转移试验所示。PAX2基因测序分析正常。结论：我们得出结论，这种新的PAX8突变是负责一个严重形式的显性遗传性CH。突变似乎与异常的泌尿生殖道。
Background: Although thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH), its molecular basis remains largely elusive. Indeed, in only a minority of cases with thyroid dysgenesis (2%-3%) was it possible to identify an underlying genetic defect. The objective of this study was to screen the PAX8 gene and the PAX2 gene in a family with six cases of CH spanning three generations and presenting urogenital malformations. Herein, we report a case series and in vitro characterization of the PAX8 gene mutation.Methods: Investigations were conducted at a tertiary care referral center. The index case was diagnosed to have congenital hypothyroidism at 7 months of age when he presented with severe impairment of suckling, constipation, and poor development. Treatment with levothyroxine corrected the symptoms and was associated with catch-up growth. His progeny, including two sons, one daughter, and two granddaughters, were affected by CH, and three of them received the diagnosis at neonatal screening. Ultrasound demonstrated normally located thyroid glands with reduced volumes. Five of the six affected family members, including the index case, had urogenital malformations, including incomplete horseshoe kidney, undescended testicles, hydrocele, and ureterocele. Strabismus was found in three out of six affected patients. No other somatic malformations were found.Results: Direct sequencing of the PAX8 gene revealed a new heterozygous mutation (c.74C>G) in all affected individuals. This mutation leads to substitution of proline with arginine at codon 25 (P25R). Fluorescence microscopy showed that P25R is normally located in the nucleus. In transient transfection studies, this mutation causes reduced transcriptional activation ability when using a luciferase reporter construct under the control of a thyroglobulin promoter. This diminished transactivation ability is due to loss of DNA binding capability as shown in electrophoresis mobility shift assay. The sequencing analysis of the PAX2 gene was normal.Conclusions: We conclude that this novel PAX8 mutation is responsible for a severe form of dominantly inherited CH. The mutation seems to be associated with abnormalities of the urogenital tract.