RESUMO
Alport syndrome is a hereditary kidney disease caused by collagen IV mutations that interfere with the formation and deposition of the α3α4α5 protomer into the glomerular basement membrane. In this issue, Yu et al. show that the chemical chaperone tauroursodeoxycholic acid prevented kidney structural changes and function decline in mice with a pathogenic missense Col4a3 mutation by increasing mutant α3α4α5 protomer glomerular basement membrane deposition and preventing podocyte apoptosis induced by endoplasmic reticulum stress.
Assuntos
Autoantígenos , Colágeno Tipo IV , Membrana Basal Glomerular , Nefrite Hereditária , Ácido Tauroquenodesoxicólico , Nefrite Hereditária/genética , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/patologia , Nefrite Hereditária/metabolismo , Animais , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Camundongos , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/efeitos dos fármacos , Humanos , Autoantígenos/genética , Autoantígenos/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Podócitos/efeitos dos fármacos , Podócitos/patologia , Podócitos/metabolismo , Mutação de Sentido Incorreto , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMO
Alport syndrome (AS) is characterized by progressive kidney failure, hematuria, sensorineural hearing loss, and ocular abnormalities. Pathogenic variants in the COL4A3-5 genes result in a defective deposition of the collagen IV α3α4α5 protomers in the basement membranes of the glomerulus in the kidney, the cochlea in the ear and the cornea, lens capsule and retina in the eye. The presence of a large variety of COL4A3-5 gene(s) pathogenetic variants irrespective of the mode of inheritance (X-linked, autosomal recessive, autosomal dominant, or digenic) with and without syndromic features is better defined as the "Alport spectrum disorder", and represents the most common cause of genetic kidney disease and the second most common cause of genetic kidney failure. The clinical course and prognosis of individuals with AS is highly variable. It is influenced by gender, mode of inheritance, affected gene(s), type of genetic mutation, and genetic modifiers. This review article will discuss the epidemiology, classification, pathogenesis, diagnosis, clinical course with genotype-phenotype correlations, and current and upcoming treatment of patients with AS. It will also review current recommendations with respect to when to evaluate for hearing loss or ophthalmologic abnormalities.
Assuntos
Nefrite Hereditária , Nefrite Hereditária/genética , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/terapia , Humanos , Colágeno Tipo IV/genéticaRESUMO
Purpose: The purpose of this study was to investigate the ocular morphological characteristics of Col4a3-/- mice as a model of Alport syndrome (AS) and the potential pathogenesis. Methods: The expression of collagen IV at 8, 12, and 21 weeks of age was evaluated by immunohistochemistry in wild-type (WT) and Col4a3-/- mice. Hematoxylin and eosin (H&E) staining and thickness measurements were performed to assess the thickness of anterior lens capsule and retina. Ultrastructure analysis of corneal epithelial basement membrane, anterior lens capsule, internal limiting membrane (ILM), and retinal pigment epithelium (RPE) basement membrane was performed using transmission electron microscopy. Finally, Müller cell activation was evaluated by glial fibrillary acidic protein (GFAP) expression. Results: Collagen IV was downregulated in the corneal epithelial basement membrane and ILM of Col4a3-/- mice. The hemidesmosomes of Col4a3-/- mice corneal epithelium became flat and less electron-dense than those of the WT group. Compared with those of the WT mice, the anterior lens capsules of Col4a3-/- mice were thinner. Abnormal structure was detected at the ILM Col4a3-/- mice, and the basal folds of the RPE basement membrane in Col4a3-/- mice were thicker and shorter. The retinas of Col4a3-/- mice were thinner than those of WT mice, especially within 1000 µm away from the optic nerve. GFAP expression enhanced in each age group of Col4a3-/- mice. Conclusions: Our results suggested that Col4a3-/- mice exhibit ocular anomalies similar to patients with AS. Additionally, Müller cells may be involved in AS retinal anomalies. Translational Relevance: This animal model could provide an opportunity to understand the underlying mechanisms of AS ocular disorders and to investigate potential new treatments.
Assuntos
Membrana Basal , Colágeno Tipo IV , Modelos Animais de Doenças , Camundongos Knockout , Nefrite Hereditária , Animais , Nefrite Hereditária/patologia , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/deficiência , Camundongos , Membrana Basal/metabolismo , Membrana Basal/patologia , Membrana Basal/ultraestrutura , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/ultraestrutura , Microscopia Eletrônica de Transmissão , Camundongos Endogâmicos C57BL , Cápsula do Cristalino/metabolismo , Cápsula do Cristalino/patologia , Cápsula do Cristalino/ultraestrutura , Epitélio Corneano/patologia , Epitélio Corneano/ultraestrutura , Epitélio Corneano/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/genética , Retina/patologia , Retina/metabolismo , Retina/ultraestrutura , Autoantígenos/genética , Autoantígenos/metabolismo , Células Ependimogliais/patologia , Células Ependimogliais/metabolismo , Células Ependimogliais/ultraestrutura , Imuno-Histoquímica , MasculinoRESUMO
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
Assuntos
Glomerulosclerose Segmentar e Focal , Síndrome Nefrótica , Humanos , Síndrome Nefrótica/genética , Síndrome Nefrótica/diagnóstico , Glomerulosclerose Segmentar e Focal/genética , Estudo de Associação Genômica Ampla , Nefrite Hereditária/genética , Nefrite Hereditária/diagnóstico , Predisposição Genética para DoençaAssuntos
Colágeno Tipo IV , Modelos Animais de Doenças , Terapia Genética , Nefrite Hereditária , Nefrite Hereditária/terapia , Nefrite Hereditária/genética , Terapia Genética/métodos , Humanos , Colágeno Tipo IV/genética , Animais , Mutação , Vetores Genéticos , Técnicas de Transferência de Genes , Camundongos , Membrana Basal/metabolismoRESUMO
BACKGROUND: Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. METHODS: We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). RESULTS: We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same. CONCLUSIONS: Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.
Assuntos
Autoantígenos , Colágeno Tipo IV , Nefrite Hereditária , Linhagem , Humanos , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Colágeno Tipo IV/genética , Autoantígenos/genética , Feminino , Masculino , Adulto , Mutação , Sequenciamento do Exoma , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Células HEK293RESUMO
Alport syndrome and autosomal dominant polycystic kidney disease are monogenic causes of chronic kidney disease and end-stage kidney failure. We present a case of a man in his 60s with progressive chronic kidney disease, bilateral sensorineural hearing loss and multiple renal cysts. Genetic analysis revealed a heterozygous variant in COL4A3 (linked to Alport syndrome) and in the GANAB gene (associated with a milder form of autosomal dominant polycystic kidney disease). Although each variant confers a mild risk of developing end-stage kidney disease, the patient presented a pronounced and accelerated progression of chronic kidney disease, which goes beyond what would be predicted by adding up their individual effects. This suggests a potential synergic effect of both variants, which warrants further investigation.
Assuntos
Colágeno Tipo IV , Nefrite Hereditária , Rim Policístico Autossômico Dominante , Humanos , Nefrite Hereditária/genética , Nefrite Hereditária/complicações , Nefrite Hereditária/diagnóstico , Masculino , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/complicações , Colágeno Tipo IV/genética , Pessoa de Meia-Idade , Autoantígenos/genética , Progressão da Doença , Falência Renal Crônica/genética , Falência Renal Crônica/etiologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnósticoRESUMO
BACKGROUND: Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD). METHODS: This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival. RESULTS: A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group (p = 0.027). Patients with missense variants had higher renal survival (p = 0.023). Hearing loss was associated with lower renal survival (p < 0.001). CONCLUSIONS: Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.
Assuntos
Colágeno Tipo IV , Estudos de Associação Genética , Falência Renal Crônica , Nefrite Hereditária , Humanos , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Feminino , Masculino , Colágeno Tipo IV/genética , Adulto , Pessoa de Meia-Idade , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Mutação , Estudos Retrospectivos , AutoantígenosRESUMO
COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.
Assuntos
Apoptose , Autoantígenos , Colágeno Tipo IV , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Camundongos Transgênicos , Mutação , Nefrite Hereditária , Ácido Tauroquenodesoxicólico , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nefrite Hereditária/genética , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/patologia , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Apoptose/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismoRESUMO
Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.
Assuntos
Colágeno Tipo IV , Nefrite Hereditária , Adulto , Feminino , Humanos , Masculino , Colágeno Tipo IV/genética , Mutação da Fase de Leitura , Nefrite Hereditária/genética , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/patologia , Linhagem , Fenótipo , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/diagnóstico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/diagnósticoRESUMO
Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFß1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
Assuntos
Nefrite Hereditária , Podócitos , Camundongos , Animais , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Podócitos/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Membrana Basal Glomerular/metabolismo , Células-Tronco/metabolismoRESUMO
Alport syndrome is one of the most common inherited kidney diseases caused by mutations in the type â £ collagen genes. It has a complex pattern of inheritance and diverse clinical manifestations, and severe cases will rapidly progress to end-stage kidney disease. With the rapid development of genetic testing technology, there is a deeper understanding of the genetic spectrum of Alport syndrome, the effectiveness of clinical therapies, and the prediction of disease prognosis. Therefore, the purpose of the article is to introduce the advances in the diagnosis and treatment of Alport syndrome, aiming to improve the early diagnosis and standardized treatment of this disease.
Assuntos
Colágeno Tipo IV , Mutação , Nefrite Hereditária , Nefrite Hereditária/terapia , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Humanos , Colágeno Tipo IV/genética , Testes Genéticos , Prognóstico , Falência Renal Crônica/terapia , Falência Renal Crônica/genética , Falência Renal Crônica/diagnósticoRESUMO
BACKGROUND: Alport syndrome (AS) is characterised by haematuria, proteinuria, a gradual decline in kidney function, hearing loss, and eye abnormalities. The disease is caused by mutations in COL4An (n = 3, 4, 5) that encodes 3-5 chains of type IV collagen in the glomerular basement membrane. AS has three genetic models: X-linked, autosomal recessive, and autosomal dominant. The most common type of AS is X-linked AS, which is caused by COL4A5. METHODS: We enrolled children with renal insufficiency and a family history of kidney disorders. The proband was identified using whole-exome sequencing. Sanger sequencing was performed to verify the mutation site. Minigene technology was used to analyse the influence of mutant genes on pre-mRNA shearing, and the Iterative Threading ASSEmbly Refinement (I-TASSER) server was used to analyse the protein structure changes. RESULTS: The proband, together with her mother and younger brother, displayed microscopic haematuria and proteinuria, Pathological examination revealed mesangial hyperplasia and sclerosis. A novel mutation (NM_000495.5 c.4298-8G > A) in the intron of the COL4A5 gene in the proband was discovered, which was also present in the proband's mother, brother, and grandmother. In vitro minigene expression experiments verified that the c.4298-8G > A mutation caused abnormal splicing, leading to the retention of six base pairs at the end of intron 46. The I-TASSER software predicted that the mutation affected the hydrogen-bonding structure of COL4A5 and the electrostatic potential on the surface of the protein molecules. CONCLUSIONS: Based on the patient's clinical history and genetic traits, we conclude that the mutation at the splicing site c.4298-8G > A of the COL4A5 gene is highly probable to be the underlying cause within this particular family. This discovery expands the genetic spectrum and deepens our understanding of the molecular mechanisms underlying AS.
Assuntos
Colágeno Tipo IV , Mutação , Nefrite Hereditária , Linhagem , Splicing de RNA , Adulto , Criança , Feminino , Humanos , Masculino , Povo Asiático/genética , China , Colágeno Tipo IV/genética , População do Leste Asiático , Nefrite Hereditária/genética , Nefrite Hereditária/patologiaRESUMO
Alport syndrome has been linked to three different genes, that is, COL4A3, COL4A4 and COL4A5. It is characterized by progressive and non-specific glomerulosclerosis with irregular thickening of the glomerular basement membrane (GBM). At times, the histopathologic picture is dominated by lesions that are consistent with focal and segmental glomerulosclerosis or IgA nephropathy. Here, we report the cases of two related individuals (mother and son) who were diagnosed with COL4A5-related Alport syndrome due to a missense variant (p.Gly1170Ser) in a G-X-Y repeat and found to present the same highly unusual histopathological abnormalities on their kidney biopsies. One of the abnormalities shared, which does not appear to have been reported, was reduced COL4A5 immunolabeling that was limited to Bowman's capsule even though the ultrastructure of the GBM was distorted. The other abnormality was superimposed segmental IgA deposition in both individuals, accompanied by mesangial changes in the mother. We feel that these findings provide novel insight into the mechanisms of disease manifestation in Alport syndrome. They suggest, in particular, that collagen expression and/or assemblies in Bowman's capsule is more vulnerable to missense mutations in COL4A5 than elsewhere in the kidney. Our findings also suggest that certain coinherited gene polymorphisms act as unexpectedly important phenotypic determinants in COL4A-related disorders.
Assuntos
Colágeno Tipo IV , Membrana Basal Glomerular , Mutação de Sentido Incorreto , Nefrite Hereditária , Adulto , Humanos , Pessoa de Meia-Idade , Biópsia , Cápsula Glomerular/patologia , Colágeno Tipo IV/genética , Predisposição Genética para Doença , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/ultraestrutura , Imunoglobulina A , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Linhagem , FenótipoRESUMO
BACKGROUND: Hereditary nephritis (HN), including Alport syndrome (AS) and thin basement membrane nephropathy (TBMN), is a rare genetic cause of hematuria. A definitive diagnosis requires electron microscopy (EM). Therefore, the clinical characteristics of these conditions are less known. This study aimed to determine the percentage and clinicopathological features of HN in patients from a referral center in Iran. METHODS: We checked kidney biopsy reports from 2007 to 2021 and extracted cases with HN. Fresh specimens of the cases diagnosed in the last two years were stained by immunofluorescence (IF) for collagen type IV alpha chains. EM findings in these cases were re-evaluated and categorized as diffuse glomerular basement membrane (GBM) thinning, definite, and suspicious features of AS. RESULTS: We analyzed 3884 pathology reports of kidney biopsies from 2007 to 2021 and identified 210 patients (5.4%) with HN, with a mean age of 13.78±12.42 years old. Hematuria with proteinuria (53.3%), isolated hematuria (44.2%), and proteinuria with hematuria and increased creatinine (2.5%) were found in these patients. The re-evaluation of EM findings revealed GBM thinning, definite, and suspicious findings of AS in 37.5%, 43.8%, and 18.8% cases, respectively. The most common diagnosis in 32 cases after the IF study was X-linked AS (71.9%), and 6.2% of cases were autosomal recessive AS. TBMN and autosomal dominant AS remained the differential diagnoses in 21.9%. CONCLUSION: It was found that EM is helpful for the primary diagnosis of patients with definite AS. Immunostaining improves the diagnostic sensitivity for the differentiation of those with suspicious EM findings and determines the inheritance pattern. However, a multidisciplinary approach for a subset of cases is required for the best diagnosis and management.
Assuntos
Nefrite Hereditária , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Hematúria/etiologia , Irã (Geográfico)/epidemiologia , Proteinúria , Encaminhamento e Consulta , Biópsia , RimRESUMO
BACKGROUND: Alport syndrome (AS) is a genetically heterogeneous disorder resulting from mutations in the collagen IV genes COL4A3, COL4A4, and COL4A5. The genetic diagnosis of AS is very important to make precise diagnosis and achieve optimal outcomes. METHODS: In this study, 16 Chinese families with suspected AS were recruited after pedigree analysis, and the clinical presentations were analyzed by a nephrologist. The genetic diagnosis was performed by whole-exome sequencing (WES) and the disease-causing variants were confirmed by Sanger sequencing. RESULTS: The cohort of probands included seven men and nine women, with a mean age of 19.9 years. Pathological analysis showed slight-to-moderate mesangial proliferation, and thin basement membrane was the main findings. Pathogenic variants were revealed by WES in each family, and the co-segregation with renal presentation was confirmed by PCR. In addition, RT-PCR analysis showed that the intronic variant led to aberrant splicing. CONCLUSION: Our findings expand the spectrum of AS gene variation, which will inform genetic diagnosis and add to the theoretical basis for the prevention of AS.
Assuntos
Nefrite Hereditária , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Povo Asiático/genética , China , Colágeno Tipo IV/genética , Rim , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genéticaRESUMO
BACKGROUND: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations. CASE PRESENTATION: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737Gâ >â T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family. CONCLUSIONS: This study has successfully identified missense mutation, c.737Gâ >â T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.
Assuntos
Falência Renal Crônica , Síndrome da Unha-Patela , Nefrite Hereditária , Humanos , Feminino , Adolescente , Fatores de Transcrição/genética , Proteínas com Homeodomínio LIM/genética , Nefrite Hereditária/genética , Mutação , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Códon , China , Proteínas de Homeodomínio/genéticaRESUMO
PURPOSE OF REVIEW: With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases". RECENT FINDINGS: Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of "benign familial hematuria" and "thin basement membrane nephropathy" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression. SUMMARY: The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
Assuntos
Nefrite Hereditária , Humanos , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Hematúria/genética , Rim/patologia , Colágeno Tipo IV/genética , MutaçãoRESUMO
Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.