Abdalla Salma A, Cymerman Urszula, Johnson Rachel M, Deber Charles M, Letarte Michelle
Cancer and Blood Research program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8, USA.
Eur J Hum Genet. 2003 Apr;11(4):279-87. doi: 10.1038/sj.ejhg.5200919.
Activin receptor-like kinase-1 (ALK-1), the gene mutated in HHT type 2 (HHT2), is a serine/threonine kinase receptor type I of the TGF-beta superfamily, specifically expressed on endothelial cells. We established an HHT2 genotype in 16 families and report nine novel mutations. These include insertions and deletions of single base pairs in exons 3, 8 and 9, as well as nonsense mutations in exons 4 and 8 of ALK-1, which would lead to premature truncation and unstable mRNA or protein. Three novel missense mutations were identified in exons 7 and 8 of the kinase domain. Five previously reported substitutions were also observed in the families analyzed. Our results bring to 36, the number of mutations associated with HHT2, and are mostly found in exons 8 and 3 followed by exons 4 and 7. To ascertain the potential functional implications of the missense mutations in the ALK-1 kinase domain, we generated a model based on the three-dimensional structure of the homologous ALK-5 kinase domain. Our data reveal that the 11 missense mutations modify residues conserved among type I receptors and alter the polarity, charge, hydrophobicity and/or size of the substituted amino-acid and likely lead to misfolded and nonfunctional proteins.
激活素受体样激酶-1（ALK-1）是2型遗传性出血性毛细血管扩张症（HHT2）中发生突变的基因，是转化生长因子-β超家族的I型丝氨酸/苏氨酸激酶受体，在内皮细胞上特异性表达。我们在16个家族中确定了HHT2基因型，并报告了9个新突变。这些突变包括外显子3、8和9中单碱基对的插入和缺失，以及ALK-1外显子4和8中的无义突变，这将导致过早截断以及不稳定的mRNA或蛋白质。在激酶结构域的外显子7和8中鉴定出3个新的错义突变。在分析的家族中还观察到5个先前报道的替换。我们的结果使与HHT2相关的突变数量达到36个，这些突变大多在外显子8和3中发现，其次是外显子4和7。为了确定ALK-1激酶结构域中错义突变的潜在功能影响，我们基于同源ALK-5激酶结构域的三维结构生成了一个模型。我们的数据表明，这11个错义突变改变了I型受体中保守的残基，改变了被取代氨基酸的极性、电荷、疏水性和/或大小，可能导致蛋白质错误折叠和无功能。
