A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Najmeh Ahangari; Amirhossein Sahebkar; Mohsen Azimi-Nezhad; Hamideh Ghazizadeh; Mohsen Moohebati; Mahmoud Ebrahim; Habibollah Esmaeili; Gordon A. Ferns; Alireza Pasdar; Majid Ghayour Mobarhan

doi:10.52547/ibj.25.5.374

A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Najmeh Ahangari, Amirhossein Sahebkar, Mohsen Azimi-Nezhad, Hamideh Ghazizadeh, Mohsen Moohebati, Mahmoud Ebrahim, Habibollah Esmaeili, Gordon A. Ferns, Alireza Pasdar, Majid Ghayour Mobarhan^* (Corresponding Author)

^*Corresponding author for this work

Applied Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses. Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin. Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.

Original language	English
Pages (from-to)	374-379
Number of pages	6
Journal	Iranian biomedical journal
Volume	25
Issue number	5
Early online date	15 May 2021
DOIs	https://doi.org/10.52547/ibj.25.5.374
Publication status	Published - 1 Sept 2021

Bibliographical note

This work was supported by Mashhad University of Medical Sciences, Mashhad, Iran through a grant (no. 951825), as a Ph.D. thesis project. The authors gratefully acknowledge the participated families.

Keywords

Genetic research
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypercholesterolemia
LDLRAP1

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title = "A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia",

abstract = "Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses. Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin. Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.",

keywords = "Genetic research, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, LDLRAP1",

author = "Najmeh Ahangari and Amirhossein Sahebkar and Mohsen Azimi-Nezhad and Hamideh Ghazizadeh and Mohsen Moohebati and Mahmoud Ebrahim and Habibollah Esmaeili and Ferns, {Gordon A.} and Alireza Pasdar and {Ghayour Mobarhan}, Majid",

note = "This work was supported by Mashhad University of Medical Sciences, Mashhad, Iran through a grant (no. 951825), as a Ph.D. thesis project. The authors gratefully acknowledge the participated families.",

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doi = "10.52547/ibj.25.5.374",

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T1 - A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

AU - Ahangari, Najmeh

AU - Sahebkar, Amirhossein

AU - Azimi-Nezhad, Mohsen

AU - Ghazizadeh, Hamideh

AU - Moohebati, Mohsen

AU - Ebrahim, Mahmoud

AU - Esmaeili, Habibollah

AU - Ferns, Gordon A.

AU - Pasdar, Alireza

AU - Ghayour Mobarhan, Majid

N1 - This work was supported by Mashhad University of Medical Sciences, Mashhad, Iran through a grant (no. 951825), as a Ph.D. thesis project. The authors gratefully acknowledge the participated families.

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses. Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin. Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.

AB - Background: familial hypercholesterolemia (FH), a hereditary disorder, is caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. This study has assessed genetic variants in a family, clinically diagnosed with FH. Methods: A family was recruited from MASHAD study in Iran with possible FH based on the Simon Broom criteria. The DNA sample of an affected individual (proband) was analyzed using whole exome sequencing, followed by bioinformatics and segregation analyses. Results: A novel splice site variant (c.345-2A>G) was detected in the LDLRAP1 gene, which was segregated in all affected family members. Moreover, HMGCR rs3846662 g.23092A>G was found to be homozygous (G/G) in the proband, probably leading to reduced response to simvastatin and pravastatin. Conclusion: LDLRAP1 c.345-2A>G could alter the phosphotyrosine-binding domain, which acts as an important part of biological pathways related to lipid metabolism.

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KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors

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A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia

Abstract

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Keywords

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