Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

TitleGenetic variants in the LAMA5 gene in pediatric nephrotic syndrome.
Publication TypeJournal Article
Year of Publication2019
AuthorsBraun, DA, Warejko, JK, Ashraf, S, Tan, W, Daga, A, Schneider, R, Hermle, T, Jobst-Schwan, T, Widmeier, E, Majmundar, AJ, Nakayama, M, Schapiro, D, Rao, J, Schmidt, JMagdalena, Hoogstraten, CA, Hugo, H, Bakkaloglu, SA, Kari, JA, Desoky, SEl, Daouk, G, Mane, S, Lifton, RP, Shril, S, Hildebrandt, F
JournalNephrol Dial Transplant
Date Published2019 03 01

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-α5, 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.

Alternate JournalNephrol. Dial. Transplant.
PubMed ID29534211
PubMed Central IDPMC6399483
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States