Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities

• Published in: Human molecular genetics 2004-11, Vol.13 (21), p.2625-2632
• Main Authors: Zenker, Martin, Aigner, Thomas, Wendler, Olaf, Tralau, Tim, Müntefering, Horst, Fenski, Regina, Pitz, Susanne, Schumacher, Valérie, Royer-Pokora, Brigitte, Wühl, Elke, Cochat, Pierre, Bouvier, Raymonde, Kraus, Cornelia, Mark, Karlheinz, Madlon, Henry, Dötsch, Jörg, Rascher, Wolfgang, Maruniak-Chudek, Iwona, Lennert, Thomas, Neumann, Luitgard M, Reis, André
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Blotting, Western; Consanguinity; DNA Mutational Analysis; Eye Abnormalities; Female; Genetic Linkage; Genetic Markers; Glomerular Mesangium - pathology; Haplotypes; Homozygote; Humans; Immunohistochemistry; Laminin - chemistry; Laminin - deficiency; Lod Score; Male; Microsatellite Repeats; Molecular Sequence Data; Nephrosis - congenital; Nephrosis - pathology; Pedigree; Polymorphism, Genetic; Sclerosis - pathology; Sequence Homology, Amino Acid
• ISSN: 0964-6906

Congenital nephrotic syndrome (CNS) is clinically and genetically heterogeneous, with mutations in WT1, NPHS1 and NPHS2 accounting for part of cases. We recently delineated a new autosomal recessive entity comprising CNS with diffuse mesangial sclerosis and distinct ocular anomalies with microcoria as the leading clinical feature (Pierson syndrome). On the basis of homozygosity mapping to markers on chromosome 3p14-p22, we identified homozygous or compound heterozygous mutations of LAMB2 in patients from five unrelated families. Most disease-associated alleles were truncating mutations. Using immunohistochemistry and western blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin beta2 expression in kidney and other tissues studied. Laminin beta2 is known to be abundantly expressed in the glomerular basement membrane (GBM) where it is thought to play a key role in anchoring as well as differentiation of podocyte foot processes. Lamb2 knockout mice were reported to exhibit congenital nephrosis in association with anomalies of retina and neuromuscular junctions. By studying ocular laminin beta2 expression in unaffected controls, we detected the strongest expression in the intraocular muscles corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in patients. Moreover, we present first clinical evidence of severe impairment of vision and neurodevelopment due to LAMB2 defects. Our current data suggest that human laminin beta2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between GBM and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.