一个大型遗传性血影细胞增多症家族中 SPTB 的新型剪接位点变异。
A novel essential splice site variant in SPTB in a large hereditary spherocytosis family.
机构信息
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA.
Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
出版信息
Mol Genet Genomic Med. 2021 May;9(5):e1641. doi: 10.1002/mgg3.1641. Epub 2021 May 4.
BACKGROUND
We studied a large family with 22 individuals affected with autosomal dominant hereditary spherocytosis (HS).
METHODS
Genome-wide linkage, whole-genome sequencing (WGS), Sanger sequencing, RT-PCR, and ToPO TA cloning analyses were performed.
RESULTS
We revealed a heterozygous G>A transition in the 14q23 locus, at position +1 of the intron 8 donor splice site of the spectrin beta, erythrocytic (SPTB) gene. This splice variant (SPTB c.1064+1G>A) was confirmed by Sanger sequencing and showed complete co-segregation with HS in the family. Further RT-PCR reactions and sequencing analysis indicated that the variant leads to the exclusion of exon 8 and subsequent frameshift in exon 9 and a premature stop codon in SPTB. Translation of the altered allele would lead to a truncation with a loss of all spectrin repeat domains in SPTB protein.
CONCLUSION
This variant is novel and has not been found in any databases. We propose that this splice variant explains the spherocytosis phenotype observed in this large family.
背景
我们研究了一个有 22 名常染色体显性遗传性血影细胞增多症（HS）患者的大家族。
方法
进行了全基因组连锁、全基因组测序（WGS）、Sanger 测序、RT-PCR 和 ToPO TA 克隆分析。
结果
我们在 14q23 位置发现了一个杂合的 G>A 转换，位于 8 号内含子供体位点+1 的剪接位点 spectrin beta，erythrocytic（SPTB）基因。该剪接变体（SPTB c.1064+1G>A）通过 Sanger 测序得到证实，并在家族中与 HS 完全共分离。进一步的 RT-PCR 反应和测序分析表明，该变体导致 8 号外显子缺失，随后 9 号外显子发生移码，并在外显子 9 中产生一个提前终止密码子，导致 SPTB 蛋白缺失所有 spectrin 重复结构域。
结论
该变体是新的，在任何数据库中都没有发现。我们提出，这种剪接变体解释了在这个大家庭中观察到的球形细胞增多症表型。
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