Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum

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 beta2, 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 beta2 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.

Figure 1

LAMB2 gene, laminin β2 protein domains, and distribution of known mutations. a, Genomic representation of the human LAMB2 gene. Vertical bars represent exons. Untranslated regions are shown in reduced height. Coloring corresponds to functional protein domains with grey color in parts of exon 1 and 2 encoding the signal peptide. Numerals within the boxes indicate exon numbers. Location of truncating mutations (nonsense, frameshift) and splice site mutations are indicated by arrows on top of the cartoon in black and blue, respectively. Positions of missense mutations and small in frame deletions are indicated by arrows at the bottom of the cartoon and show obvious clustering in exons 2 to 7. b, In its biologically active form laminin β2 is part of a heterotrimeric complex shown here exemplarily as laminin-521. Laminin α5 and γ1 chains are depicted in light and dark grey, respectively. Coloring of the human laminin β2 chain corresponds to functional protein domains: LN, laminin N-terminal globular domain; LEa/b, laminin EGF-like modules; LF, domain IV, globular domain; LCC, laminin coiled coil domain; Lβ, Laminin β loop; LG, C-terminal globular modules (belonging to α chain). Positions of non-truncating mutations are indicated by asterisks. Most of them affect the LN domain (yellow asterisks), while one is located in the first EGF-like module (pink) and another one in the LCC domain (orange). c, The first EGF-like module (LEa1) is shown in detail with letters corresponding to the one letter amino acid code. The highly conserved cysteine residues are highlighted and connecting lines indicate disulfide bonds. The mutated Cys-321 is shown in pink.

Figure 2

Age of onset of gross proteinuria/nephrosis (a) and age of onset of end stage renal disease (ESRD) (b) are plotted on the Y axis in two genotypic classes: patients with either nonsense or frameshift mutations on both alleles (“truncating”) and patients with a missense mutation or small in frame deletion on at least one allele (“missense”). Each bullet represents one individual patient. Grey filled circles indicate the age when the respective patient developed NS and ESRD, respectively, while open circles represent patients who have not developed this feature (nephrosis or ESRD) at the given age of their last follow-up examination. Black bullets in (b) represent the age of death of those patients who died without having developed ESRD. Boxes indicate the range between upper and lower quartiles. Black horizontal line represents median. Whiskers reach from maximum to minimum excluding outliers. Arrowheads represent observations out of the range of the diagram (age in months given in parentheses).