Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis

Abstract

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2. Whole exome sequencing and Sanger sequencing were performed. Functional analysis of the identified mutations has been done. Whole exome sequencing identified two pairs of variants in LPL gene in the proband 1 (c.162C>A and c.1322+1G>A) and proband 2 (c.835C>G and c.1322+1G>A). The substitution (c.162C>A) leads to the formation of a truncated (p.Cys54*) LPL protein. The substitution (c.835C>G) leads to the replacement of leucine to valine (p.Leu279Val). The splice donor site mutation (c.1322+1G>A) leads to the formation of alternative transcripts with the loss of 134 bp in exon 8 of the LPL gene. The proband 1 and his younger son also harbouring a heterozygous variant (c.553G>T; p.Gly185Cys) in APOA5 gene. The relative expression level of the mutated LPL mRNA (c.162C>A, c.835C>G and c.1322+1G>A) showed significant differences compared to wild-type LPL mRNA, suggesting that all these three mutations affect the transcription of LPL mRNA. These three mutations (c.162C>A, c.835C>G and c.1322+1G>A)showed noticeably decreased LPL activity in cell culture medium but not in cell lysates.Here, we identified three mutations in LPL gene which causes severe hypertriglyceridaemia with acute pancreatitis in Chinese patients. We also described the significance of whole exome sequencing for identifying the candidate gene and disease-causing mutation in patients with severe hypertriglyceridaemia and acute pancreatitis.

Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next‐generation sequencing

“…Only variants with a frequency below 1 percent were selected. Previously reported mutations that have been described in Human Gene Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar) as pathogenic or likely pathogenic were given the highest priority 13 . Prediction of the consequence of point mutations was obtained from at least three online databases, namely SIFT (https://sift.bii.a-star.edu.sg/), Polyphen2 (http://genetics.bwh.harvard.edu/pph2/), and MutationTaster (http://www.mutationtaster.org/).…”

“…gov/clinvar) as pathogenic or likely pathogenic were given the highest priority. 13 Prediction of the consequence of point mutations was obtained from at least three online databases, namely SIFT (https:// sift.bii.a-star.edu.sg/), Polyphen2 (http://genet ics.bwh.harva rd.edu/ pph2/), and MutationTaster (http://www.mutat ionta ster.org/). In case of intronic variants, Human Splicing Finder (HSF) (http://www.…”

A novel COL2A1 mutation causing spondyloepiphyseal dysplasia congenita in a Chinese family

“…to analyze harmful mutations. The quality control system [3][4][5][6] for identifying the candidate variants is shown in Figure 3 and Table 2.…”

A novel mutation in NF1 gene of patient with Neurofibromatosis type 1: A case report and functional study

“…Custom gene panel was designed and used to capture targeted sequence, covering all exons and flanking sequence (including the 10 bp of introns) of 187 genes which are associated with growth and development of children (Table S1). The procedure for preparation of libraries was consistent with standard operating protocols previously described (An et al, 2019;Dai et al, 2019;Han et al, 2020;Zhang, Chen, et al, 2020). The average mean depth for the targeted regions was 370, and 84.4% of the covered exons had ≥10 reads.…”