Jorge Alexander A de Lima, Menezes Filho Hamilton C de, Lins Theresa S Soares, Guedes Dulce Rondini, Damiani Durval, Setian Nuvarte, Arnhold Ivo J Prado, Mendonça Berenice B de
Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina, Universidade de São Paulo, SP.
Arq Bras Endocrinol Metabol. 2005 Jun;49(3):384-9. doi: 10.1590/s0004-27302005000300009. Epub 2006 Mar 16.
We studied the growth hormone receptor (GHR) gene in 6 patients with Laron syndrome (LS) from 4 unrelated families. Exons 2 to 10 were amplified by PCR using specific intronic pairs of primers. The PCR products were directly sequenced. Our results showed that all 6 patients carried a homozygous GAG>GAA mutation in codon 180 of exon 6. This mutation did not change the translated amino acid, but created an abnormal splice site deleting 8 amino acids from the extracellular domain of GHR. Members of all 4 kindreds with the E180splice mutation were genotyped for 4 polymorphic intragenic sites: The retention or exclusion of exon 3, single nucleotide polymorphisms present in exons 6 and 10, and intron 9 polymorphic site. All 6 patients presented the same haplotype. The E180splice mutation was first described in a population of Spanish descendants from the Andes of Southern Ecuador. This mutation was also found in oriental Jewish patients from Israel. Our families share the same intron-9 haplotype observed in Ecuadorian and Israeli patients. We conclude that the E180splice mutation is an important cause of LS in Brazil and there is probably a founder effect since our patients, Ecuadorian and Israeli patients share the same haplotype in intron 9.
我们研究了来自4个无关家庭的6例拉伦综合征（LS）患者的生长激素受体（GHR）基因。使用特定的内含子引物对，通过聚合酶链反应（PCR）扩增外显子2至10。PCR产物直接测序。我们的结果显示，所有6例患者在第6外显子的第180密码子处均携带纯合的GAG>GAA突变。该突变未改变翻译后的氨基酸，但产生了一个异常剪接位点，导致GHR细胞外结构域缺失8个氨基酸。对所有4个携带E180剪接突变的家族成员进行了4个基因内多态性位点的基因分型：外显子3的保留或缺失、外显子6和10中存在的单核苷酸多态性以及内含子9多态性位点。所有6例患者呈现相同的单倍型。E180剪接突变最初在来自厄瓜多尔南部安第斯山脉的西班牙后裔人群中被描述。该突变在来自以色列的东方犹太患者中也有发现。我们的家族与在厄瓜多尔和以色列患者中观察到的相同内含子9单倍型相同。我们得出结论，E180剪接突变是巴西LS的一个重要病因，并且可能存在奠基者效应，因为我们的患者、厄瓜多尔和以色列患者在内含子9中共享相同的单倍型。
