Mutations in the human laminin β2 (LAMB2) gene and the associated phenotypic spectruma

Abstract

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin b2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin b2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Rapid Detection of Monogenic Causes of Childhood-Onset Steroid-Resistant Nephrotic Syndrome

“…An age distribution of the identified mutations is shown in Supplemental Figure 5. Because there is a strong phenotype-genotype correlation for patients with mutations in NS (41,42), the clinical diagnosis for each patient was considered to determine whether the putative genetic cause found in our mutation analysis was truly disease-causing. In a previously published highthroughput analysis, the decision of whether a genetic variant was disease-causing wasn't sufficiently clarified (43).…”

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…Missense-mutations of the a2 and a1 LN domains have been found to cause a mild neuromuscular and retinal defects respectively, the latter associated with a partial reduction in the ability of the LN domain to bind to its bLN and gLN partners (Patton et al 2008;Edwards et al 2010). Missense mutations clustered within the laminin b2LN domain are a cause of Pierson disease, a syndrome characterized by congenital nephrotic syndrome, ocular abnormalities, and neurologic deficits (Matejas et al 2010). …”

Laminin β2 Gene Missense Mutation Produces Endoplasmic Reticulum Stress in Podocytes

“…[1][2][3] Pierson syndrome is caused by mutations in the laminin b2 gene (LAMB2). 4 Laminin, type IV collagen, nidogen, and sulfated proteoglycans comprise the glomerular basement membrane (GBM), 5 an unusually thick BM formed by fusion of distinct BMs assembled by podocytes and glomerular endothelial cells.…”