A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy

BMC Medical Genetics
Zuhair N Al-HassnanJehad Alburaiki

Abstract

Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM. In a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect. A region of homozygosity (ROH) on chromosome 8q24.13-24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES ...Continue Reading

References

Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·Y WangR Thalmann
Feb 24, 2001·Genome Biology·E T Kipreos, M Pagano
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·M D GomesA L Goldberg
Jun 28, 2005·Nucleic Acids Research·Emidio CapriottiRita Casadio
Aug 19, 2007·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·David O TaylorMarshall I Hertz
Aug 19, 2007·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Mark M BoucekMarshall I Hertz
Oct 24, 2009·Cardiovascular Research·Giulia MeariniLucie Carrier
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Sep 25, 2010·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Ray E HershbergerJill D Siegfried
Mar 19, 2011·Current Opinion in Cardiology·Saskia Schlossarek, Lucie Carrier
Jul 9, 2011·Circulation Research·Donghoon Lee, Alfred Goldberg
May 3, 2014·The Journal of Clinical Investigation·Tania ZagliaMarco Sandri

❮ Previous
Next ❯

Citations

Oct 4, 2016·Biochemical and Biophysical Research Communications·Nan YangWei Kong
Sep 14, 2017·Clinical Chemistry and Laboratory Medicine : CCLM·Fang YuanYi-Qing Yang
Feb 16, 2018·Heart and Vessels·Yu-Min SunYi-Qing Yang
Sep 7, 2019·International Journal of Molecular Sciences·Andreas BrodehlHendrik Milting
Feb 16, 2021·Frontiers in Physiology·Alessandro EvangelistiFederica Del Monte
Sep 11, 2021·Frontiers in Pharmacology·Ly PoroskÜlo Langel

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
genotyping
exome sequencing
PCR
biopsy

Software Mentioned

Polyphen2
Ensembl Genome Browser
2ovq
Gene Hunter Easy Linkage Analysis
GATK
Mutant
GeneDistiller2
- Aligner
GeneHunter Easy
Ensembl genome browsers

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.