title: Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy.
abstract: Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. Patients with MAD develop two patterns of lipodystrophy: type A pattern, with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions; and type B pattern, with a more generalized loss of sc fat involving the face, trunk, and extremities. Recently, affected patients from five consanguineous Italian pedigrees with partial lipodystrophy (type A) were reported to have a homozygous R527H mutation in LMNA (lamin A/C) gene. We carried out mutational analysis of LMNA in affected patients from six pedigrees. Affected patients from two pedigrees with type A lipodystrophy had the homozygous R527H mutation in LMNA. The other four affected subjects who had type B lipodystrophy did not have any mutation in the exons and splice site junctions of LMNA; RNA extracted from lymphoblasts of two of these patients also revealed normal sequence. In these four subjects, sequencing of other known genes implicated in lipodystrophies, i.e. AGPAT2, Seipin, and PPARG also revealed no substantial alterations. We conclude that MAD is a genetically and phenotypically heterogeneous disorder. Besides LMNA gene, other as yet unmapped loci could be linked to MAD.
authors.affiliation: Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Vinaya
authors.initials: V
authors.lastname: Simha
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Elif Arioglu
authors.initials: EA
authors.lastname: Oral
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000097:blood / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance; D034904:Lamin Type A / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000097:blood / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008334:Mandible / Q000002:abnormalities*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014280:Triglycerides / Q000097:blood
chemical_list: D034904:Lamin Type A; D014280:Triglycerides; C440308:lamin C