Diabetic kidney disease(DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, ...Diabetic kidney disease(DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate(eG FR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called "non-albuminuric renal impairment" is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eG FR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.展开更多
Diabetic complications including diabetic nephropathy,retinopathy,and neuropathy are as major causes of morbidity and mortality in diabetes individuals worldwide and current therapies are still unsatisfactory.One of t...Diabetic complications including diabetic nephropathy,retinopathy,and neuropathy are as major causes of morbidity and mortality in diabetes individuals worldwide and current therapies are still unsatisfactory.One of the reasons for failure to develop effective treatment is the lack of fundamental understanding for underlying mechanisms.Genetic studies are powerful tools to dissect disease mechanism.The heritability(h2) was estimated to be 0.3-0.44 for diabetic nephropathy and 0.25-0.50 for diabetic retinopathy respectively.Previous linkage studies for diabetic nephropathy have identified overlapped linkage regions in 1q43-44,3q21-23,3q26,10p12-15,18q22-23,19q13,22q11-12.3 in multiple ethnic groups.Genome-wide association studies(GWAS) of diabetic nephropathy have been conducted in several populations.However,most of the identified risk loci could not be replicated by independent studies with a few exceptions including those in ELMO1,FRMD3,CARS,MYO16/IRS2,and APOL3-MYH9 genes.Functional studies of these genes revealed the involvement of cytoskeleton reorganization(especially non-muscle type myosin),phagocytosis of apoptotic cells,fibroblast migration,insulin signaling,and epithelial clonal expansion in the pathogenesis of diabetic nephropathy.Linkage analyses of diabetic retinopathy overlapped only in 1q36 region and current results from GWAS for diabetic retinopathy are inconsistent.Conclusive results from genetic studies for diabetic neuropathy are lacking.For now,small sample sizes,confounding by population stratification,different phenotype definitions between studies,ethnic-specific associations,the influence of environmental factors,and the possible contribution of rare variants may explain the inconsistencies between studies.展开更多
CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remai...CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1.Here,using repeat-primed-polymerase chain reaction and long-read sequencing,we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1,typically presenting with oculopharyngodistal myopathy.The CGG repeat expansions range from 161 to 669 repeat units.Most of the patients present with ptosis,restricted eye movements,dysphagia,dysarthria,and diffuse limb muscle weakness.Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging.Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles.Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity,suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis.Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.展开更多
文摘Diabetic kidney disease(DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate(eG FR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called "non-albuminuric renal impairment" is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eG FR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
文摘Diabetic complications including diabetic nephropathy,retinopathy,and neuropathy are as major causes of morbidity and mortality in diabetes individuals worldwide and current therapies are still unsatisfactory.One of the reasons for failure to develop effective treatment is the lack of fundamental understanding for underlying mechanisms.Genetic studies are powerful tools to dissect disease mechanism.The heritability(h2) was estimated to be 0.3-0.44 for diabetic nephropathy and 0.25-0.50 for diabetic retinopathy respectively.Previous linkage studies for diabetic nephropathy have identified overlapped linkage regions in 1q43-44,3q21-23,3q26,10p12-15,18q22-23,19q13,22q11-12.3 in multiple ethnic groups.Genome-wide association studies(GWAS) of diabetic nephropathy have been conducted in several populations.However,most of the identified risk loci could not be replicated by independent studies with a few exceptions including those in ELMO1,FRMD3,CARS,MYO16/IRS2,and APOL3-MYH9 genes.Functional studies of these genes revealed the involvement of cytoskeleton reorganization(especially non-muscle type myosin),phagocytosis of apoptotic cells,fibroblast migration,insulin signaling,and epithelial clonal expansion in the pathogenesis of diabetic nephropathy.Linkage analyses of diabetic retinopathy overlapped only in 1q36 region and current results from GWAS for diabetic retinopathy are inconsistent.Conclusive results from genetic studies for diabetic neuropathy are lacking.For now,small sample sizes,confounding by population stratification,different phenotype definitions between studies,ethnic-specific associations,the influence of environmental factors,and the possible contribution of rare variants may explain the inconsistencies between studies.
文摘CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1.Here,using repeat-primed-polymerase chain reaction and long-read sequencing,we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1,typically presenting with oculopharyngodistal myopathy.The CGG repeat expansions range from 161 to 669 repeat units.Most of the patients present with ptosis,restricted eye movements,dysphagia,dysarthria,and diffuse limb muscle weakness.Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging.Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles.Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity,suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis.Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.
