Atypical progeroid syndrome due to heterozygous missense LMNA mutations

Abhimanyu Garg, Lalitha Subramanyam, Anil K. Agarwal, Vinaya Simha, Benjamin Levine, Maria Rosaria D'Apice, Giuseppe Novelli, Yanick Crow

Research output: Contribution to journalArticle

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Abstract

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are wellrecognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, the senuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.

Original languageEnglish (US)
Pages (from-to)4971-4983
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number12
DOIs
StatePublished - Dec 2009

Fingerprint

Lamin Type A
Mutation
Fibroblasts
Transferases
Progeria
Skin
trichostatin A
Histone Deacetylase Inhibitors
Microscopic examination
Genes
Congenital Generalized Lipodystrophy
Acro-Osteolysis
Alopecia
Nose
Atrophy
Foot
Molecular Biology
Microscopy
Hand
prelamin A

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Atypical progeroid syndrome due to heterozygous missense LMNA mutations. / Garg, Abhimanyu; Subramanyam, Lalitha; Agarwal, Anil K.; Simha, Vinaya; Levine, Benjamin; D'Apice, Maria Rosaria; Novelli, Giuseppe; Crow, Yanick.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 12, 12.2009, p. 4971-4983.

Research output: Contribution to journalArticle

Garg, Abhimanyu ; Subramanyam, Lalitha ; Agarwal, Anil K. ; Simha, Vinaya ; Levine, Benjamin ; D'Apice, Maria Rosaria ; Novelli, Giuseppe ; Crow, Yanick. / Atypical progeroid syndrome due to heterozygous missense LMNA mutations. In: Journal of Clinical Endocrinology and Metabolism. 2009 ; Vol. 94, No. 12. pp. 4971-4983.
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AU - Levine, Benjamin

AU - D'Apice, Maria Rosaria

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AU - Crow, Yanick

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