title: A novel homozygous LMNA mutation (p.Met540Ile) causes mandibuloacral dysplasia type A.
abstract: Mandibuloacral dysplasia with type A lipodystrophy (MADA) is a rare genetic disorder inherited in an autosomal recessive fashion characterized by hypoplasia of the mandible and clavicles, acroosteolysis and lipodystrophy due to mutations in the LMNA or ZMPSTE24 genes. In the current study, we have investigated a consanguineous family clinically diagnosed with mandibuloacral dysplasia type A having an affected child for the LMNA gene alteration(s). Mother is now 15weeks pregnant, seeking advice on the health of her fetus. Peripheral blood was obtained from all family members after informed consent was achieved. Genomic DNA was isolated. The sequence of the LMNA gene, including all exons and intron boundaries was analyzed by PCR and Sanger sequencing. Chorionic villus was collected from the placenta to reveal the condition of the fetus. Molecular analysis ascertained a homozygous mutation c.1620G>A (p.M540I) in the proband and heterozygous alteration in the family. Genomic DNA isolated from the CVS was amplified using specific primers for identified deleterious mutation and analyzed by Sanger sequencing. Two pathogenic mutations c.1620G>A and c.1698C>T were identified in the fetus. Genetic counseling as well as justified rapid and sensitive genetic testing can provide reassurance for the families to prevent the high burden of genetic disorders. We have also applied several online tools including PolyPhen2, MUpro, SIFT, PoPMuSiC, Project HOPE and Mutation Taster to predict the impact of p.Met540Ile substitution as a hotspot region within LMNA. All tools showed reduction in the stability of the protein structure. We conclude that p.M540I mutation may causes disease in the homozygous state.
authors.affiliation: Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1966645643, Iran; Dept. of Medical Genetic, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1966645643, Iran. Electronic address: v.yassaee-grc@sbmu.ac.ir.
authors.forename: Vahid Reza
authors.initials: VR
authors.lastname: Yassaee
authors.affiliation: Dept. of Oral and Maxillofacial Surgery, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: arashkhojasteh@yahoo.com.
authors.forename: Arash
authors.initials: A
authors.lastname: Khojaste
authors.affiliation: Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: f.hashemigorji@gmail.com.
authors.forename: Feyzollah
authors.initials: F
authors.lastname: Hashemi-Gorji
authors.affiliation: Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: zeinab.ravesh@yahoo.com.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Ravesh
authors.affiliation: Dept. of Dermatology, Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: p.toossi@sbmu.ac.ir.
authors.forename: Parviz
authors.initials: P
authors.lastname: Toosi
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D030981:Acro-Osteolysis / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000595:Amino Acid Sequence; D003241:Consanguinity; D006720:Homozygote; D006801:Humans; D007492:Iran; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics*; D008060:Lipodystrophy / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008334:Mandible / Q000002:abnormalities*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A
keywords: Genetic counseling; Genetic testing; LMNA; Mandibuloacral dysplasia