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Human Molecular Genetics Advance Access published online on September 14, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh284
© 2004 by Oxford University Press
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Article

Human laminin {beta}2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities

Martin Zenker 1*, Thomas Aigner 2, Olaf Wendler 3, Tim Tralau 4, Horst Müntefering 4, Regina Fenski 5, Susanne Pitz 6, Valérie Schumacher 7, Brigitte Royer-Pokora 7, Elke Wühl 8, Pierre Cochat 9, Raymonde Bouvier 9, Cornelia Kraus 10, Karlheinz Mark 11, Henry Madlon 11, Jörg Dötsch 12, Wolfgang Rascher 12, Iwona Maruniak-Chudek 13, Thomas Lennert 14, Luitgard M. Neumann 5, and André Reis 10

1 Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany
2 Institute of Pathology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
3 Department of Otorhinolaryngology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
4 Department of Pediatric Pathology, University of Mainz, 55101 Mainz, Germany
5 Institute of Human Genetics, Charité Universitary Medicine Berlin, Humboldt University, 13353 Berlin, Germany
6 Department of Ophthalmology, University of Mainz, 55101 Mainz, Germany
7 Institute of Human Genetics, University of Dusseldorf, 40001 Dusseldorf, Germany
8 Department of Pediatric Nephrology, University Children's Hospital, 69120 Heidelberg, Germany
9 Département de Pédiatrie and Laboratoire d'Anatomie Pathologique, Hôpital Edouard-Herriot, Université Claude-Bernard, 69437 Lyon, France
10 Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
11 Department of Obstetrics and Prenatal Medicine and Children's Hospital, Klinikum Weiden, 92605 Weiden, Germany
12 University Children's Hospital, Pediatric Nephrology, 91054 Erlangen, Germany
13 Department of Neonatal Intensive Care, Medical University of Silesia, 40-752 Katowice, Poland
14 Department of Pediatric Nephrology, Humboldt University, 13353 Berlin, Germany

* To whom correspondence should be addressed. E-mail: mzenker{at}humgenet.uni-erlangen.de.


  Abstract

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 leading clinical feature (Pierson syndrome). Based on 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. By immunohistochemistry and western-blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin {beta}2 expression in kidney and other tissues studied. Laminin {beta}2 is known to be abundantly expressed in the glomerular basement membrane 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 {beta}2 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 suggests that human laminin {beta}2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between glomerular basement membrane and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.


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