Kopp P, Arseven O K, Sabacan L, Kotlar T, Dupuis J, Cavaliere H, Santos C L, Jameson J L, Medeiros-Neto G
Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern University, Chicago, Illinois 60611, USA.
J Clin Endocrinol Metab. 1999 Jan;84(1):336-41. doi: 10.1210/jcem.84.1.5398.
Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness. The gene mutated in Pendred's syndrome, PDS (Pendred's syndrome gene), was cloned very recently and encodes the putative sulfate transporter pendrin. Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness. In this study, 41 individuals from a large, highly inbred pedigree from Northeastern Brazil were examined for features of Pendred's syndrome. Linkage studies and sequence analysis of the coding region of the PDS gene were performed with DNA from 36 individuals. The index patient, with the classical triad of deafness, positive perchlorate test, and goiter, was found to be homozygous for a deletion of thymidine 279 in exon 3, resulting in a frameshift and a premature stop codon at amino acid 96. This alteration resulted in truncation of the protein in the first transmembrane domain. Two other patients with deafness were found to be homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wild type allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the PDS gene mutation; 3 were heterozygous and 3 were homozygous for the wild type allele, suggesting a probable distinct genetic cause for their deafness. All 3 homozygous individuals for the PDS mutation had goiters. However, goiters were also found in 10 heterozygous individuals and in 6 individuals without the PDS mutation and are most likely caused by iodine deficiency. In conclusion, we identified a novel mutation in the PDS gene causing Pendred's syndrome. The comparison of phenotype and genotype reveals, however, that phenocopies generated by distinct environmental and/or genetic causes are present in this kindred and that the diagnosis of Pendred's syndrome may be difficult without molecular analysis.
彭德莱德综合征是一种常染色体隐性疾病，其特征为甲状腺肿、碘有机化受损以及先天性感音神经性耳聋。最近克隆了在彭德莱德综合征中发生突变的基因PDS（彭德莱德综合征基因），它编码假定的硫酸盐转运体pendrin。彭德莱德综合征可能占遗传性听力损失病例的10%，并且在一个非综合征性耳聋的家族中也发现了pendrin突变。在本研究中，对来自巴西东北部一个大型高度近亲家系的41名个体进行了彭德莱德综合征特征检查。对36名个体的DNA进行了PDS基因编码区的连锁研究和序列分析。索引患者具有耳聋、高氯酸盐试验阳性和甲状腺肿的典型三联征，被发现外显子3中胸腺嘧啶279缺失纯合，导致移码并在氨基酸96处出现提前终止密码子。这种改变导致蛋白质在第一个跨膜结构域截断。另外两名耳聋患者被发现该突变为纯合；19人为杂合，14人为野生型等位基因纯合。令人惊讶的是，这个家族中的6名耳聋个体并非PDS基因突变纯合；3人为杂合，3人为野生型等位基因纯合，提示他们耳聋可能有不同的遗传原因。所有3名PDS突变纯合个体均有甲状腺肿。然而，在10名杂合个体和6名无PDS突变个体中也发现了甲状腺肿，很可能是由碘缺乏引起的。总之，我们在PDS基因中鉴定出一个导致彭德莱德综合征的新突变。然而，表型和基因型的比较显示，该家族中存在由不同环境和/或遗传原因产生的表型模拟，并且如果没有分子分析，彭德莱德综合征的诊断可能会很困难。
