Collagen (<i>COL4A</i>) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis

Gast, Christine; Pengelly, Reuben J.; Lyon, M.; Bunyan, David J.; Seaby, Eleanor G.; Graham, Nikki; Venkat‐Raman, Gopalakrishnan; Ennis, Sarah

doi:10.1093/ndt/gfv325

Cited by 232 publications

(234 citation statements)

References 58 publications

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“…By far, the most common example of this is the newly identified association with APOL1 as discussed below. Other genetic risk loci include PDSS1 (71) and numerous others (72,73). More are likely to be discovered in the near future.…”

Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

434

366

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Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

434

366

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“…Nearly 100% of patients with congenital onset and 44% with infantile onset of NS have podocyte gene mutations, and the overall mutation detection rate is as high as 52% in steroid-resistant pediatric NS patients (3). The leading mutated podocyte genes include laminin β2 (LAMB2) causing congenital NS and Pierson syndrome and collagen IV α chain (COL4A) underlying Alport syndrome (AS) and focal segmental glomerulosclerosis (FSGS) (4). Emerging evidence has demonstrated that podocyte ER stress may be an important functional link from genetic mutations to disease phenotype in primary NS.…”

Section: Introductionmentioning

confidence: 99%

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

Park¹,

Manson²,

Molina³

et al. 2017

JCI Insight

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“…One mother showed focal segmental glomerulosclerosis (FSGS) on kidney biopsy. Presentation of Alport syndrome with isolated proteinuria [17] and FSGS in male and female patients [18][19][20][21] have been reported before. The etiology of FSGS may be that it develops secondary to the abnormalities in the GBM, or alternatively that FSGS belongs to a spectrum of diseases of the GBM primarily caused by a COL4A3-5 mutation.…”

Section: Discussionmentioning

confidence: 99%

Diagnosing Alport Syndrome: Lessons from the Pediatric Ward

Vos

Zietse

Geel

et al. 2018

Nephron

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Background: Alport syndrome is a rare inheritable kidney disease frequently leading to end-stage kidney disease in young adults. Patients could benefit from early recognition of the disease. In several children with Alport syndrome, a parent was noticed to have renal symptoms attributed to another renal disease. Aim: To review the renal history of the closest family members of a cohort of pediatric patients with genetically proven Alport syndrome. Methods: The medical records of all children with genetically proven Alport syndrome identified at our pediatric nephrology department in the last 20 years were reviewed, with focus on the medical history of affected parents. Results: Twenty-three children with Alport syndrome from 21 different families were identified. Eight of 21 probands had family member(s) with renal symptoms attributed to other diseases. In these, a type IV collagen mutation was determined only after the manifestation of Alport syndrome in their child. One proband presented atypically with acute membrano-proliferative glomerulo-nephritis. Only 3 out of 8 probands with a known family history of Alport syndrome had been intentionally screened for this disease. A COL4A5 mutation was found in 18 probands, COL4A3 in 2, and COL4A4 in 1. Each family showed private mutations; 17 out of 21 mutations were novel. Conclusions: Atypical presentation of Alport syndrome was quite common in mothers of our pediatric patients. To enable earlier diagnosis of Alport syndrome, nephrologists should look for a positive diagnosis in any patient with persistent renal symptoms, especially if there is a positive family history of (any) renal disease.

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Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis

Abstract: We show that collagen IV mutations, including COL4A5, frequently underlie FSGS and should be considered, particularly with a positive family history. Targeted NGS improves diagnostic efficiency by investigating many candidate genes in parallel.

Cited by 232 publications

References 58 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

Diagnosing Alport Syndrome: Lessons from the Pediatric Ward

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