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Submitted on December 30, 2004
Accepted on June 29, 2005
Division of Nutrition and Metabolic Diseases (A.K.A., A.G.), Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, U.S.A. and Faculty of Medicine, Department of Pediatrics (O. C., F. O., H. O.), Ege University, Izmir, Turkey
* To whom correspondence should be addressed. E-mail: Abhimanyu.garg{at}utsouthwestern.edu.
Context. 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, lipodystrophy and mottled cutaneous pigmentation. MAD patients with type A lipodystrophy with loss of sc (sc) fat from the extremities and normal or slight excess in the neck and truncal regions have been previously reported to carry a homozygous Arg527His mutation in LMNA (Lamin A/C) gene. Among those with type B pattern of lipodystrophy with generalized loss of sc fat, we recently reported a patient carrying compound heterozygous mutations in an endoprotease, zinc metalloproteinase (ZMPSTE24), gene which is involved in post-translational processing of prelamin A to mature lamin A.
Objective. To carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy.
Design. Descriptive Case Reports.
Setting. Referral Center.
Patients. A male and a female patient with MAD who belonged to two pedigrees from Turkey.
Interventions. None
Main Outcome Measures. Genotype-Phenotype relationships.
Results. We now report that both these patients have a novel homozygous missense mutation (c.1586 C>T) in LMNA which replaces a well-conserved residue alanine at position 529 to valine. Intragenic single nucleotide polymorphisms revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both the affected subjects suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different than that seen in women with MAD and Arg527His LMNA mutation.
Conclusions. We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype.
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