Abstract
Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia disorder. ANK1 mutations account for most HS cases, but pathogenicity analysis and functional research have not been widely performed for these mutations. In this study, in order to confirm diagnosis, gene mutation was screened in two unrelated Chinese families with HS by a next‐generation sequencing (NGS) panel and then confirmed by Sanger sequencing. Two novel heterozygous mutations (c.C841T, p.R281X and c.T290G, p.L97R) of the ANK1 gene were identified in the two families respectively. Then, the pathogenicity of the two new mutations and two previously reported ANK1 mutations (c.C648G, p.Y216X and c.G424T, p.E142X) were studied by in vitro experiments. The four mutations increased the osmotic fragility of cells, reduced the stabilities of ANK1 proteins and prevented the protein from localizing to the plasma membrane and interacting with SPTB and SLC4A1. We classified these four mutations into disease‐causing mutations for HS. Thus, conducting the same mutation test and providing genetic counselling for the two families were meaningful and significant. Moreover, the identification of two novel mutations enriches the ANK1 mutation database, especially in China.
Highlights
Hereditary spherocytosis (HS), one of the most common monogenic haemolytic anaemia diseases, is characterized by spherical‐shaped erythrocytes in the peripheral blood of patients
Hereditary spherocytosis is caused by mutations of erythro‐ cyte membrane‐related genes, including ANK1, SPTB, SPTA1, SLC4A1 and EPB42, following an autosomal dominant (AD) and autosomal recessive inheritance mode.[8]
These results indicated that cell rupture occurred more in ANK1 mutant cells, leading to higher cell os‐ motic fragility
Summary
Hereditary spherocytosis (HS), one of the most common monogenic haemolytic anaemia diseases, is characterized by spherical‐shaped erythrocytes in the peripheral blood of patients. Hereditary spherocytosis is caused by mutations of erythro‐ cyte membrane‐related genes, including ANK1 (ankyrin 1; OMIM 612641), SPTB (spectrin, beta, erythrocytic; OMIM 182870), SPTA1 (spectrin, alpha, erythrocytic 1; OMIM 182860), SLC4A1 (solute carrier family 4, member 1; OMIM 109270) and EPB42 (protein 4.2, erythrocytic; OMIM 177070), following an autosomal dominant (AD) and autosomal recessive inheritance mode.[8]. Mutations in these genes usually produce decreased surface area per unit volume of erythrocytes or dysfunction of the erythrocyte membrane, leading to the detachment of the lipid bilayer from the spectrin‐based cy‐ toskeleton. We carried out functional research in vitro to further confirm the pathogenicity of four ANK1 mutations, including the two novel mutations and two previously reported mutations (c.G424T, p.E142X and c.C648G, p.Y216X) in a Chinese population.[7]
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