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Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome
- Source :
- Nephrology, Dialysis, Transplantation, 34, 3, pp. 485-493, Nephrology, Dialysis, Transplantation, 34, 485-493
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- Item does not contain fulltext BACKGROUND: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, approximately 15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In approximately 30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-alpha5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. METHODS: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. RESULTS: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. CONCLUSION: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.
- Subjects :
- Adult
Male
Nephrotic Syndrome
Adolescent
DNA Mutational Analysis
030232 urology & nephrology
030204 cardiovascular system & hematology
medicine.disease_cause
Young Adult
03 medical and health sciences
0302 clinical medicine
Gene mapping
Exome Sequencing
medicine
Humans
Hypoalbuminemia
Child
Gene
Exome sequencing
Genetics
Transplantation
Mutation
business.industry
Homozygote
Infant, Newborn
Infant
Prognosis
medicine.disease
Disease gene identification
Pedigree
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
Phenotype
Nephrology
Child, Preschool
Female
Laminin
ORIGINAL ARTICLES
business
Nephrotic syndrome
Immunosuppressive Agents
Orthologous Gene
Subjects
Details
- ISSN :
- 14602385 and 09310509
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Nephrology Dialysis Transplantation
- Accession number :
- edsair.doi.dedup.....7a53ba772a59a25af6ff9acced0ad710