Mutations in the human laminin beta2 (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 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.
Matejas
Verena
V
Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany.
Hinkes
Bernward
B
Alkandari
Faisal
F
Al-Gazali
Lihadh
L
Annexstad
Ellen
E
Aytac
Mehmet B
MB
Barrow
Margaret
M
Bláhová
Kveta
K
Bockenhauer
Detlef
D
Cheong
Hae Il
HI
Maruniak-Chudek
Iwona
I
Cochat
Pierre
P
Dötsch
Jörg
J
Gajjar
Priya
P
Hennekam
Raoul C
RC
Janssen
Françoise
F
Kagan
Mikhail
M
Kariminejad
Ariana
A
Kemper
Markus J
MJ
Koenig
Jens
J
Kogan
Jillene
J
Kroes
Hester Y
HY
Kuwertz-Bröking
Eberhard
E
Lewanda
Amy F
AF
Medeira
Ana
A
Muscheites
Jutta
J
Niaudet
Patrick
P
Pierson
Michel
M
Saggar
Anand
A
Seaver
Laurie
L
Suri
Mohnish
M
Tsygin
Alexey
A
Wühl
Elke
E
Zurowska
Aleksandra
A
Uebe
Steffen
S
Hildebrandt
Friedhelm
F
Antignac
Corinne
C
Zenker
Martin
M
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
D007797:Laminin; C058783:laminin beta2