Cangul Hakan, Darendeliler Feyza, Saglam Yaman, Kucukemre Banu, Kendall Michaela, Boelaert Kristien, Barrett Timothy G, Maher Eamonn R
Department of Medical Genetics, Bahcesehir University School of Medicine , Istanbul , Turkey .
Endocr Res. 2015;40(3):146-50. doi: 10.3109/07435800.2014.967354. Epub 2014 Oct 20.
Absract Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family.
Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing.
The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date.
This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the amino-terminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.
摘要目的：据报道，甲状腺过氧化物酶（TPO）基因突变可导致先天性甲状腺功能减退症（CH），本研究旨在确定来自近亲家庭的两名患病儿童先天性甲状腺功能减退症的遗传基础。
由于CH在近亲/多病例家庭中通常以常染色体隐性方式遗传，我们采用了遗传连锁研究和候选基因靶向测序的两阶段策略。首先，我们使用微卫星标记研究该家庭与任何已知CH位点的潜在遗传连锁，然后通过桑格测序筛选连锁基因中的突变。
该家庭显示出与TPO基因的潜在连锁，我们在两名患有完全碘有机化缺陷（TIOD）的病例中均检测到一个无义突变（Y55X）。该突变在家族中与疾病状态共分离。Y55X是文献中报道的TPO基因外显子2中唯一的截短突变，导致该基因迄今为止已知的最早终止密码子。
本研究证实了Y55X突变的致病性，并表明TPO基因氨基末端编码区的无义突变可完全消除TPO酶的功能，导致TIOD。因此，它有助于建立与该突变相关的强基因型/表型相关性。它还强调了分子遗传学研究在CH的明确诊断和准确分类中的重要性。
