Mutations in the human laminin Delta b2 (LAMB2) gene and the associated phenotypic spectrum

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 la...

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Published in:Human mutation 2010-09, Vol.31 (9), p.992-1002
Main Authors: Matejas, Verena, Hinkes, Bernward, Alkandari, Faisal, Al-Gazali, Lihadh, Annexstad, Ellen, Aytac, Mehmet B, Barrow, Margaret, Blahova, Kveta, Bockenhauer, Detlef, Cheong, Hae Il, Maruniak-Chudek, Iwona, Cochat, Pierre, Dotsch, Jorg, Gajjar, Priya, Hennekam, Raoul C, Janssen, Francoise, Kagan, Mikhail, Kariminejad, Ariana, Kemper, Markus J, Koenig, Jens, Kogan, Jillene, Kroes, Hester Y, Kuwertz-Broking, Eberhard, Lewanda, Amy F, Medeira, Ana, Muscheites, Jutta, Niaudet, Patrick, Pierson, Michel, Saggar, Anand, Seaver, Laurie, Suri, Mohnish, Tsygin, Alexey, Wuhl, Elke, Zurowska, Aleksandra, Uebe, Steffen, Hildebrandt, Friedhelm, Antignac, Corinne, Zenker, Martin
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Language:English
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Summary: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 Delta *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 Delta *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. Hum Mutat 31:992-1002, 2010. [copy 2010 Wiley-Liss, Inc.
ISSN:1098-1004
DOI:10.1002/humu.21304