ClinVar Genomic variation as it relates to human health

Hutchinson-Gilford Progeria Syndrome In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome (HGPS; 176670), Eriksson et al. (2003) found an identical de novo 1824C-T transition, resulting in a silent gly-to-gly mutation at codon 608 (G608G) within exon 11 of the LMNA gene. This substitution created an exonic consensus splice donor sequence and results in activation of a cryptic splice site and deletion of 50 codons of prelamin A. This mutation was not identified in any of the 16 parents available for testing. De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice site activation mutation (1824C-T+1819-1968del) in 2 HGPS patients. Immunocytochemical analyses of lymphocytes from 1 patient using specific antibodies directed against lamin A/C, lamin A, and lamin B1 showed that most cells had strikingly altered nuclear sizes and shapes, with envelope interruptions accompanied by chromatin extrusion. Lamin A was detected in 10 to 20% of HGPS lymphocytes. Only lamin C was present in most cells, and lamin B1 was found in the nucleoplasm, suggesting that it had dissociated from the nuclear envelope due to the loss of lamin A. Western blot analysis showed 25% of normal lamin A levels, and no truncated form was detected. Cao and Hegele (2003) confirmed the observations of Eriksson et al. (2003) using the same cell lines. They referred to this mutation as 2036C-T. D'Apice et al. (2004) confirmed paternal age effect and demonstrated a paternal origin of the 2036C-T mutation in 3 families with isolated cases of Hutchinson-Gilford progeria. By light and electron microscopy of fibroblasts from HGPS patients carrying the 1824C-T mutation, Goldman et al. (2004) found significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsened as the HGPS cells aged in culture, and their severity correlated with an apparent accumulation of mutant protein, which Goldman et al. (2004) designated LA delta-50. Introduction of LA delta-50 into normal cells by transfection or protein injection induced the same changes. Goldman et al. (2004) hypothesized that the alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LA delta-50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication. In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005) identified the G608G mutation. In lymphocyte DNA from the parents, normal wildtype alleles were observed in the father, but a low signal corresponding to the mutant allele was detected in the mother's DNA. A segregation study confirmed that the patient's mutation was transmitted from the mother, who showed germline and somatic mosaicism without manifestations of HGPS. Glynn and Glover (2005) studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and G608G-mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities (as seen in HGPS fibroblasts), and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, which caused the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. Glynn and Glover (2005) proposed that abnormal farnesylation of progerin may play a role in the cellular phenotype in HGPS cells, and suggested that FTIs may represent a therapeutic option for patients with HGPS. In cells from a female patient with HGPS due to the 1824C-T mutation, Shumaker et al. (2006) found that the inactive X chromosome showed loss of histone H3 trimethylation of lys27 (H3K27me3), a marker for facultative heterochromatin, as well as loss of histone H3 trimethylation of lys9 (H3K9me3), a marker of pericentric constitutive heterochromatin. Other alterations in epigenetic control included downregulation of the EZH2 methyltransferase (601573), upregulation of pericentric satellite III repeat transcripts, and increase in the trimethylation of H4K20. The epigenetic alterations were observed before the pathogenic changes in nuclear shape. The findings indicated that the mutant LMNA protein alters sites of histone methylation known to regulate heterochromatin and provided evidence that the rapid aging phenotype of HGPS reflects aspects of normal aging at the molecular level. Moulson et al. (2007) demonstrated that HGPS cells with the common 1824C-T LMNA mutation produced about 37.5% of wildtype full-length transcript, which was higher than previous estimates (Reddel and Weiss, 2004). Using real-time RT-PCR, Rodriguez et al. (2009) found that progerin transcripts were expressed in dermal fibroblasts cultured from normal controls, but at a level more than 160-fold lower than that detected in dermal fibroblasts cultured from HGPS patients. The level of progerin transcripts, but not of lamin A or lamin C transcripts, increased in late-passage cells from both normal controls and HGPS patients. Restrictive Dermopathy 2 In an infant (P2) with restrictive dermopathy (RSDM2; 619793), Navarro et al. (2004) identified the 1824C-T transition in the LMNA gene in heterozygous state. (less)

Hutchinson-Gilford Progeria Syndrome In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome (HGPS; 176670), Eriksson et al. (2003) found an identical de novo 1824C-T transition, resulting in a silent gly-to-gly mutation at codon 608 (G608G) within exon 11 of the LMNA gene. This substitution created an exonic consensus splice donor sequence and results in activation of a cryptic splice site and deletion of 50 codons of prelamin A. This mutation was not identified in any of the 16 parents available for testing. De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice site activation mutation (1824C-T+1819-1968del) in 2 HGPS patients. Immunocytochemical analyses of lymphocytes from 1 patient using specific antibodies directed against lamin A/C, lamin A, and lamin B1 showed that most cells had strikingly altered nuclear sizes and shapes, with envelope interruptions accompanied by chromatin extrusion. Lamin A was detected in 10 to 20% of HGPS lymphocytes. Only lamin C was present in most cells, and lamin B1 was found in the nucleoplasm, suggesting that it had dissociated from the nuclear envelope due to the loss of lamin A. Western blot analysis showed 25% of normal lamin A levels, and no truncated form was detected. Cao and Hegele (2003) confirmed the observations of Eriksson et al. (2003) using the same cell lines. They referred to this mutation as 2036C-T. D'Apice et al. (2004) confirmed paternal age effect and demonstrated a paternal origin of the 2036C-T mutation in 3 families with isolated cases of Hutchinson-Gilford progeria. By light and electron microscopy of fibroblasts from HGPS patients carrying the 1824C-T mutation, Goldman et al. (2004) found significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsened as the HGPS cells aged in culture, and their severity correlated with an apparent accumulation of mutant protein, which Goldman et al. (2004) designated LA delta-50. Introduction of LA delta-50 into normal cells by transfection or protein injection induced the same changes. Goldman et al. (2004) hypothesized that the alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LA delta-50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication. In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005) identified the G608G mutation. In lymphocyte DNA from the parents, normal wildtype alleles were observed in the father, but a low signal corresponding to the mutant allele was detected in the mother's DNA. A segregation study confirmed that the patient's mutation was transmitted from the mother, who showed germline and somatic mosaicism without manifestations of HGPS. Glynn and Glover (2005) studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and G608G-mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities (as seen in HGPS fibroblasts), and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, which caused the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. Glynn and Glover (2005) proposed that abnormal farnesylation of progerin may play a role in the cellular phenotype in HGPS cells, and suggested that FTIs may represent a therapeutic option for patients with HGPS. In cells from a female patient with HGPS due to the 1824C-T mutation, Shumaker et al. (2006) found that the inactive X chromosome showed loss of histone H3 trimethylation of lys27 (H3K27me3), a marker for facultative heterochromatin, as well as loss of histone H3 trimethylation of lys9 (H3K9me3), a marker of pericentric constitutive heterochromatin. Other alterations in epigenetic control included downregulation of the EZH2 methyltransferase (601573), upregulation of pericentric satellite III repeat transcripts, and increase in the trimethylation of H4K20. The epigenetic alterations were observed before the pathogenic changes in nuclear shape. The findings indicated that the mutant LMNA protein alters sites of histone methylation known to regulate heterochromatin and provided evidence that the rapid aging phenotype of HGPS reflects aspects of normal aging at the molecular level. Moulson et al. (2007) demonstrated that HGPS cells with the common 1824C-T LMNA mutation produced about 37.5% of wildtype full-length transcript, which was higher than previous estimates (Reddel and Weiss, 2004). Using real-time RT-PCR, Rodriguez et al. (2009) found that progerin transcripts were expressed in dermal fibroblasts cultured from normal controls, but at a level more than 160-fold lower than that detected in dermal fibroblasts cultured from HGPS patients. The level of progerin transcripts, but not of lamin A or lamin C transcripts, increased in late-passage cells from both normal controls and HGPS patients. Restrictive Dermopathy 2 In an infant (P2) with restrictive dermopathy (RSDM2; 619793), Navarro et al. (2004) identified the 1824C-T transition in the LMNA gene in heterozygous state. (less)