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Clear Evidence of LAMA5 Gene Biallelic Truncating Variants Causing Infantile Nephrotic Syndrome
- Source :
- Kidney360
- Publication Year :
- 2021
- Publisher :
- American Society of Nephrology, 2021.
-
Abstract
- BACKGROUND: Pathogenic 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. METHODS: We 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. RESULTS: Biallelic 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]). CONCLUSIONS: Our 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.
- Subjects :
- Collagen Type IV
Male
Nephrotic Syndrome
Nephritis, Hereditary
Compound heterozygosity
Frameshift mutation
Exon
Glomerular Basement Membrane
medicine
Missense mutation
Humans
Child
Gene
Original Investigation
Genetics
Proteinuria
business.industry
General Medicine
medicine.disease
Steroid-resistant nephrotic syndrome
Editorial
Mutation
Female
Laminin
medicine.symptom
business
Nephrotic syndrome
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Kidney360
- Accession number :
- edsair.doi.dedup.....cdbb08e3bdb5e5d4f4c74af2471e397e