title: 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.
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany.
authors.forename: Verena
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authors.lastname: Kagan
authors.forename: Ariana
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authors.lastname: Kariminejad
authors.forename: Markus J
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authors.lastname: Kemper
authors.forename: Jens
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authors.lastname: Koenig
authors.forename: Jillene
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authors.lastname: Kogan
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.forename: Eberhard
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authors.lastname: Kuwertz-Bröking
authors.forename: Amy F
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authors.lastname: Lewanda
authors.forename: Ana
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authors.lastname: Medeira
authors.forename: Jutta
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authors.lastname: Muscheites
authors.forename: Patrick
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authors.lastname: Niaudet
authors.forename: Michel
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authors.lastname: Pierson
authors.forename: Anand
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authors.lastname: Saggar
authors.forename: Laurie
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authors.lastname: Seaver
authors.forename: Mohnish
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authors.lastname: Suri
authors.forename: Alexey
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authors.lastname: Tsygin
authors.forename: Elke
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authors.lastname: Wühl
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zurowska
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Corinne
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authors.lastname: Antignac
authors.forename: Martin
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authors.lastname: Zenker
mesh_terms: D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D007797:Laminin; C058783:laminin beta2