Back to Search
Start Over
Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress.
- Source :
-
BMC cell biology [BMC Cell Biol] 2005 Jun 27; Vol. 6, pp. 27. Date of Electronic Publication: 2005 Jun 27. - Publication Year :
- 2005
-
Abstract
- Background: Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein.<br />Results: We studied a new case of a 5 year-old girl with HGPS and found a heterozygous point mutation, G608G, in LMNA. Complementary DNA sequencing of RNA showed that this mutation resulted in the deletion of 50 amino acids in the carboxyl-terminal tail domain of prelamin A. We characterized a primary dermal fibroblast cell line derived from the subject's skin. These cells expressed the mutant protein and exhibited a normal growth rate at early passage in primary culture but showed alterations in nuclear morphology. Expression levels and overall distributions of nuclear lamins and emerin, an integral protein of the inner nuclear membrane, were not dramatically altered. Ultrastructural analysis of the nuclear envelope using electron microscopy showed that chromatin is in close association to the nuclear lamina, even in areas with abnormal nuclear envelope morphology. The fibroblasts were hypersensitive to heat shock, and demonstrated a delayed response to heat stress.<br />Conclusion: Dermal fibroblasts from a subject with HGPS expressing a mutant truncated lamin A have dysmorphic nuclei, hypersensitivity to heat shock, and delayed response to heat stress. This suggests that the mutant protein, even when expressed at low levels, causes defective cell stability, which may be responsible for phenotypic abnormalities in the disease.
- Subjects :
- Cell Nucleus chemistry
Cell Nucleus pathology
Cell Nucleus ultrastructure
Cells, Cultured
Child, Preschool
Chromatin
Female
Fibroblasts ultrastructure
Humans
Lamin Type A analysis
Lamins analysis
Membrane Proteins analysis
Nuclear Envelope pathology
Nuclear Proteins
Progeria pathology
Sequence Deletion
Skin pathology
Thymopoietins analysis
Fibroblasts pathology
Heat Stress Disorders genetics
Lamin Type A genetics
Point Mutation
Progeria genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2121
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- BMC cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 15982412
- Full Text :
- https://doi.org/10.1186/1471-2121-6-27