Mandibuloacral Dysplasia is Caused by a Mutation in LMNA-encoding Lamin A/C

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2002 Jun 21

PMID 12075506

Citations 156

Authors

Giuseppe Novelli

Antoine Muchir

Federica Sangiuolo

Anne Helbling-Leclerc

Maria Rosaria DApice

Catherine Massart

Francesca Capon

Paolo Sbraccia

Massimo Federici

Renato Lauro

Cosimo Tudisco

Rosanna Pallotta

Gioacchino Scarano

Bruno Dallapiccola

Luciano Merlini

Gisele Bonne

Affiliations

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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.

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