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

TY - JOUR

T1 - Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum.

AU - Matejas, Verena

AU - Hinkes, Bernward

AU - Alkandari, Faisal

AU - Al-Gazali, Lihadh

AU - Annexstad, Ellen

AU - Aytac, Mehmet B

AU - Barrow, Margaret

AU - Bláhová, Kveta

AU - Bockenhauer, Detlef

AU - Cheong, Hae Il

AU - Maruniak-Chudek, Iwona

AU - Cochat, Pierre

AU - Dötsch, Jörg

AU - Gajjar, Priya

AU - Hennekam, Raoul C

AU - Janssen, Françoise

AU - Kagan, Mikhail

AU - Kariminejad, Ariana

AU - Kemper, Markus J.

AU - Koenig, Jens

AU - Kogan, Jillene

AU - Kroes, Hester Y

AU - Kuwertz-Bröking, Eberhard

AU - Lewanda, Amy F

AU - Medeira, Ana

AU - Muscheites, Jutta

AU - Niaudet, Patrick

AU - Pierson, Michel

AU - Saggar, Anand

AU - Seaver, Laurie

AU - Suri, Mohnish

AU - Tsygin, Alexey

AU - Wühl, Elke

AU - Zurowska, Aleksandra

AU - Uebe, Steffen

AU - Hildebrandt, Friedhelm

AU - Antignac, Corinne

AU - Zenker, Martin

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 31

SP - 992

EP - 1002

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 9

M1 - 9

ER -