title: Novel nonsense mutation in the PTRF gene underlies congenital generalized lipodystrophy in a consanguineous Saudi family.
abstract: Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare, monogenic disorders characterized by loss of sub-cutaneous fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, cardiac arrhythmias, impaired metabolism and mental retardation. Four different but overlapping phenotypes (CGL1-4) have been identified, which are caused by mutations in AGPAT2 at 9q34.3, BSCL2 at 11q13, CAV1 at 7q31.1, and PTRF at 17q21.2. In this study, we performed genome-wide homozygosity mapping of two affected and one unaffected subject in a Saudi family using a 300K HumanCytoSNPs12v12.1 array with the Illumina iScan system. A common homozygous region at chromosome 17q22.1, from 34.4 to 45.3 Mb, was identified in both the affected individuals. The region is flanked by SNPs rs139433362 and rs185263326, which encompass the PTRF gene. Bidirectional DNA sequencing of the PTRF gene covering all of the coding exons and exon-intron boundaries was performed in all family members. Sequencing analysis identified a novel homozygous nonsense mutation in the PTRF gene (c.550G>T; p.Glu184*), leading to a premature stop codon. To the best of our knowledge, we present a novel mutation of PTRF from Saudi Arabia and our findings broaden the mutation spectrum of PTRF in the familial CGL4 phenotype. Homozygosity mapping coupled with candidate gene sequencing is an effective tool for identifying the causative pathogenic variants in familial cases.
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Medical Genetics and Molecular Biology Unit, Biochemistry Department, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25000, Pakistan. Electronic address: mjelani@kau.edu.sa.
authors.forename: Musharraf
authors.initials: M
authors.lastname: Jelani
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Mona Mohammad
authors.initials: MM
authors.lastname: Almramhi
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Human Genetics Research Centre, Division of Biomedical Sciences (BMS), St. George's, University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Hussein Sheikh Ali
authors.initials: HS
authors.lastname: Mohamoud
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Khadijah
authors.initials: K
authors.lastname: Bakur
authors.affiliation: Department of Pediatrics, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors.forename: Waseem
authors.initials: W
authors.lastname: Anshasi
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jumana Yousuf
authors.initials: JY
authors.lastname: Al-Aama
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA
chemical_list: C497835:CAVIN1 protein, human; D018389:Codon, Nonsense; D016601:RNA-Binding Proteins
keywords: Lipodystrophy; Novel mutation; PTRF; Saudi Arabia