Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N) patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.
 ...
PMID:Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS). 2173 62

The recent elucidation of rare human genetic disorders resulting from mutations in ectonucleotide pyrophosphotase/phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), has highlighted the vital importance of this molecule in human health and disease. Generalised arterial calcification in infants (GACI), a frequently lethal disease, has been reported in recessive inactivating mutations in ENPP1. Recent findings have also linked hypophosphataemia to a lack of NPP1 function. A number of human genetic studies have indicated that NPP1 is a vital regulator that influences a wide range of tissues through various signalling pathways and when disrupted can lead to significant pathology. The function of Enpp1 has been widely studied in rodent models, where both the mutant tiptoe walking (ttw/ttw) mouse and genetically engineered Enpp1(-/-) mice show significant alterations in skeletal and soft tissue mineralisation, calcium/phosphate balance and glucose homeostasis. These models therefore provide important tools with which to study the potential mechanisms underpinning the human diseases associated with altered NPP1. This review will focus on the recent advances in our current knowledge of the actions of NPP1 in relation to bone disease, cardiovascular pathologies and diabetes. A fuller understanding of the mechanisms through which NPP1 exerts its pathological effects may stimulate the development of novel therapeutic strategies for patients at risk from the devastating clinical outcomes associated with disrupted NPP1 function.
 ...
PMID:New insights into NPP1 function: lessons from clinical and animal studies. 2284 19