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Human Molecular Genetics Advance Access originally published online on September 14, 2004
Human Molecular Genetics 2004 13(21):2625-2632; doi:10.1093/hmg/ddh284
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved

Human laminin ß2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities

Martin Zenker1,*, Thomas Aigner2, Olaf Wendler3, Tim Tralau4, Horst Müntefering4, Regina Fenski6, Susanne Pitz5, Valérie Schumacher7, Brigitte Royer-Pokora7, Elke Wühl8, Pierre Cochat9, Raymonde Bouvier9, Cornelia Kraus1, Karlheinz Mark10, Henry Madlon10, Jörg Dötsch11, Wolfgang Rascher11, Iwona Maruniak-Chudek12, Thomas Lennert13, Luitgard M. Neumann6 and André Reis1

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

Received July 14, 2004; Revised August 17, 2004; Accepted September 4, 2004

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 the leading clinical feature (Pierson syndrome). On the basis of 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. Using immunohistochemistry and western blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin ß2 expression in kidney and other tissues studied. Laminin ß2 is known to be abundantly expressed in the glomerular basement membrane (GBM) 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 ß2 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 suggest that human laminin ß2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between GBM and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.

* To whom correspondence should be addressed at: Institute of Human Genetics, Schwabachanlage 10, 91054 Erlangen, Germany. Tel: +49 91318522318; Fax: +49 9131209297; Email: mzenker{at}humgenet.uni-erlangen.de


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