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Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

ABSTRACT: BACKGROUND:Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ?15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ?30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-?5, 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.

SUBMITTER: Braun DA

PROVIDER: S-EPMC6399483 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

Braun Daniela A DA Warejko Jillian K JK Ashraf Shazia S Tan Weizhen W Daga Ankana A Schneider Ronen R Hermle Tobias T Jobst-Schwan Tilman T Widmeier Eugen E Majmundar Amar J AJ Nakayama Makiko M Schapiro David D Rao Jia J Schmidt Johanna Magdalena JM Hoogstraten Charlotte A CA Hugo Hannah H Bakkaloglu Sevcan A SA Kari Jameela A JA El Desoky Sherif S Daouk Ghaleb G Mane Shrikant S Lifton Richard P RP Shril Shirlee S Hildebrandt Friedhelm F

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20190301 3

<h4>Background</h4>Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a ...[more]

PMID: 29534211

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Project description:BackgroundPathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid-resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only seven patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome, and one patient with SRNS with biallelic LAMA5 missense variants.MethodsWe conducted comprehensive gene screening of Japanese patients with severe proteinuria. With the use of targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays.ResultsBiallelic truncating variants in the LAMA5 gene (NM_005560) were detected in three patients from two families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.[Arg3078*]) and a splice site variant (c.1282 + 1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.[Arg2720*]) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin β1 and γ1 chains. Patient 4 showed SRNS at the age of 8 years, and carried compound heterozygous missense variants (c.1493C>T, p.[Ala498Val] and c.8399G>A, p.[Arg2800His]).ConclusionsOur patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathologic characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in patients with congenital/infantile nephrotic syndrome.

Dataset Information

Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

Publications

Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

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