title: Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.
abstract: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Since patients with MAD frequently have partial lipodystrophy and insulin resistance, we hypothesized that the disease may be caused by mutations in the LMNA gene. We analyzed five consanguineous Italian families and demonstrated linkage of MAD to chromosome 1q21, by use of homozygosity mapping. We then sequenced the LMNA gene and identified a homozygous missense mutation (R527H) that was shared by all affected patients. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation.
authors.affiliation: Department of Biopathology and Diagnostic Imaging, Faculty for Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Romea, Italy. novelli@med.uniroma2.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.forename: Federica
authors.initials: F
authors.lastname: Sangiuolo
authors.forename: Anne
authors.initials: A
authors.lastname: Helbling-Leclerc
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Catherine
authors.initials: C
authors.lastname: Massart
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.forename: Cosimo
authors.initials: C
authors.lastname: Tudisco
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pallotta
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics*; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006801:Humans; D034904:Lamin Type A; D034882:Lamins; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins