Mutation detectionin the endoglin gene in a family with hereditary haemorrhagic telangiectasia
Peta, Kimberly Thando
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Introduction: Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant bleeding disorder. It is characterised by the presence of mucocutaneous telangiectases, visceral arteriovenous malformations and epistaxis. The phenotype is diagnosed according to the Curaçao criteria. At a molecular level, HHT has been linked to the Endoglin, Activin kinase 1 (ALK1) and SMAD4 genes in numerous studies. The majority of studies are centred on European and American population groups. There are few publications of HHT on people of African descent, none of which are family based studies. To our knowledge, this is the first study presenting mRNA expression sequence data of the Endoglin (ENG) gene in a population of African descent. The aim of the study is to detect splice site and exon region mutations present in the ENG gene of the family members affected with HHT. Methodology: RNA was isolated from blood, stabilised in RNAlater and stored at - 20ºC using the Ribopure blood kit and TRizol® methods. The RNA was converted to cDNA that served as a template molecule for sequence mutation detection. In total 11 primer pairs were designed and used to amplify 15 exon regions of the endoglin gene. Sanger sequencing was employed to determine ENG mutations. Results: Four mutations were identified, two in exon 1, namely c.-324A>G and c.-207G>A and two missense mutations c.640G>A and c.1510G>A located in exon 5 and exon 11 were identified, respectively. The exon 1 mutation c.-324A>G is a population variant. The c.-207G>A exon 1 mutation was concluded to have no effect on the resulting amino acid and only one HHT individual harboured this mutation. The missense mutations c.640G>A and c.1510G>A were previously described in participants with and without HHT in literature, resulting in conflicting interpretations regarding HHT causality. Results from this study indicate that the latter mutations occurred in two different individuals that have been diagnosed with HHT. Conclusion: The identified mutations were present in individuals who were formerly diagnosed with HHT but none of them can be proven to be pathogenic, since it was not present in all the HHT affected family members. Future studies should focus on the mutation detection of other HHT associated genes such as SMAD4, ALK1, BMP9 and RASA1 genes in this family to decipher HHT pathogenesis in a family from African descent.