TY - JOUR
T1 - Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation
AU - Agarwal, Anil K.
AU - Kazachkova, Irina
AU - Ten, Svetlana
AU - Garg, Abhimanyu
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01-DK54387 and M01-RR00633, and by the Southwest Medical Foundation.
PY - 2008/12
Y1 - 2008/12
N2 - Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24). Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy. Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted inabnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventionson fibroblasts. Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase. Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
AB - Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24). Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy. Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted inabnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventionson fibroblasts. Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase. Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
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U2 - 10.1210/jc.2008-0123
DO - 10.1210/jc.2008-0123
M3 - Article
C2 - 18796515
AN - SCOPUS:57349129333
SN - 0021-972X
VL - 93
SP - 4617
EP - 4623
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
ER -