CONTEXT: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral 
dysplasia are well-recognized 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, these nuclear 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.