First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Abstract

Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

Increased susceptibility to oxidative stress‐ and ultraviolet A‐induced apoptosis in fibroblasts in atypical progeroid syndrome/atypical Werner syndrome with LMNA mutation

“…The D300 residue is located in the coiled-coil domain of lamin A, a region critical for lamin dimerization, suggesting that impaired lamin dimerization may be mainly associated with the pathogenesis of APS/ AWS. 3,19 Consistent with this finding, alternative splice forms of lamin A, such as progerin were not detected in APS/AWS fibroblasts with or without UVA irradiation in immunoblotting (Fig. 3b).…”

“…We previously reported that an abnormal nuclear morphology, increased aggregation of heterochromatin and decreased interchromatin granules in the nuclei of fibroblasts derived from patient with LMNA mutation were observed in immunofluorescence staining and electron microscopic analysis, suggesting that an abnormal nuclear morphology and chromatin disorganization might be associated with the pathogenesis of APS/AWS. In the current study, we showed that the protein levels of lamin A/C are lower in APS/AWS fibroblasts than in normal fibroblasts, suggesting that a reduced amount of lamin A/C may be associated with the abnormal nuclear morphology and abnormal distribution of heterochromatin in APS/AWS fibroblasts.…”

“…Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome associated with heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C . We previously reported the first Japanese case of APS/AWS with a heterozygous LMNA c.898G>A mutation in exon 5, predicted to cause a change in aspartic acid 300 into asparagine at the protein level (p.Asp300Asn, p.D300N) . A 53‐year‐old Japanese man had a history of recurrent severe cardiovascular and cerebrovascular diseases.…”

“…In addition, we identified an abnormal nuclear morphology, increased aggregation of small area of heterochromatin and a decreased number of interchromatin granules in the nuclei in fibroblasts from our APS/AWS patient in immunofluorescence staining and electron microscopic analysis, suggesting that an abnormal nuclear morphology and chromatin disorganization are potentially associated with the pathogenesis of APS/AWS. 3 Cutaneous ageing is caused by two simultaneously progressing processes, intrinsic ageing and extrinsic ageing, including photoageing.…”

Association of serum levels of antibodies against MMP1, CBX1, and CBX5 with transient ischemic attack and cerebral infarction

“…Consistently, levels of CBX1-Abs and CBX5-Abs were elevated in TIA and CI patients (Figures 3 and 4). In addition, there was an increase in the small aggregation of heterochromatin and a decrease in the level of interchromatin granules in the nuclei of fibroblasts from patients with atypical Werner syndrome (AWS), which is usually accompanied by disorders with multiple features resembling accelerated aging, mainly including vascular diseases such as aortosclerosis and DM [56, 57]. This suggests that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of AWS/DM, and studies into the functional role of HP1 family members, particularly CBX5, which has diverse roles in the nucleus, including heterochromatin packaging and euchromatic gene regulation [52, 53], may be important.…”