Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.
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.
Novelli
Giuseppe
G
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
Muchir
Antoine
A
Sangiuolo
Federica
F
Helbling-Leclerc
Anne
A
D'Apice
Maria Rosaria
MR
Massart
Catherine
C
Capon
Francesca
F
Sbraccia
Paolo
P
Federici
Massimo
M
Lauro
Renato
R
Tudisco
Cosimo
C
Pallotta
Rosanna
R
Scarano
Gioacchino
G
Dallapiccola
Bruno
B
Merlini
Luciano
L
Bonne
Gisèle
G
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
D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins