A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia

Abhimanyu Garg, Ozgur Cogulu, Ferda Ozkinay, Huseyin Onay, Anil K. Agarwal

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 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 that is involved in posttranslational processing of prelamin A to mature lamin A. Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy. Design and Setting: We studied descriptive case reports at a referral center. Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey. Main Outcome Measures: We assessed genotype-phenotype relationships. Results: We now report that both these patients have a novel homozygous missense mutation (c.1586C→T; c refers to cDNA reference sequence) in LMNA that 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 from 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.

Original languageEnglish (US)
Pages (from-to)5259-5264
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number9
DOIs
StatePublished - Sep 2005

Fingerprint

Lamin Type A
Mutation
Alanine
Phenotype
Nucleotides
Genes
Fats
Congenital Generalized Lipodystrophy
Acro-Osteolysis
Cranial Sutures
Skin Pigmentation
Lipodystrophy
Valine
Metalloproteases
Menstruation
Polymorphism
Contracture
Missense Mutation
Pedigree
Arginine

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia. / Garg, Abhimanyu; Cogulu, Ozgur; Ozkinay, Ferda; Onay, Huseyin; Agarwal, Anil K.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 9, 09.2005, p. 5259-5264.

Research output: Contribution to journalArticle

@article{da33250cdd67478a92be6f2fad0f4745,
title = "A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia",
abstract = "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 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 that is involved in posttranslational processing of prelamin A to mature lamin A. Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy. Design and Setting: We studied descriptive case reports at a referral center. Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey. Main Outcome Measures: We assessed genotype-phenotype relationships. Results: We now report that both these patients have a novel homozygous missense mutation (c.1586C→T; c refers to cDNA reference sequence) in LMNA that 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 from 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.",
author = "Abhimanyu Garg and Ozgur Cogulu and Ferda Ozkinay and Huseyin Onay and Agarwal, {Anil K.}",
year = "2005",
month = "9",
doi = "10.1210/jc.2004-2560",
language = "English (US)",
volume = "90",
pages = "5259--5264",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "9",

}

TY - JOUR

T1 - A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia

AU - Garg, Abhimanyu

AU - Cogulu, Ozgur

AU - Ozkinay, Ferda

AU - Onay, Huseyin

AU - Agarwal, Anil K.

PY - 2005/9

Y1 - 2005/9

N2 - 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 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 that is involved in posttranslational processing of prelamin A to mature lamin A. Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy. Design and Setting: We studied descriptive case reports at a referral center. Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey. Main Outcome Measures: We assessed genotype-phenotype relationships. Results: We now report that both these patients have a novel homozygous missense mutation (c.1586C→T; c refers to cDNA reference sequence) in LMNA that 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 from 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.

AB - 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 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 that is involved in posttranslational processing of prelamin A to mature lamin A. Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy. Design and Setting: We studied descriptive case reports at a referral center. Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey. Main Outcome Measures: We assessed genotype-phenotype relationships. Results: We now report that both these patients have a novel homozygous missense mutation (c.1586C→T; c refers to cDNA reference sequence) in LMNA that 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 from 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.

UR - http://www.scopus.com/inward/record.url?scp=24644473652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24644473652&partnerID=8YFLogxK

U2 - 10.1210/jc.2004-2560

DO - 10.1210/jc.2004-2560

M3 - Article

C2 - 15998779

AN - SCOPUS:24644473652

VL - 90

SP - 5259

EP - 5264

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 9

ER -