NDT Advance Access originally published online on August 18, 2006
Nephrology Dialysis Transplantation 2006 21(11):3283-3286; doi:10.1093/ndt/gfl463
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A syndrome comprising childhood-onset glomerular kidney disease and ocular abnormalities with progressive loss of vision is caused by mutated LAMB2
1Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany and 2Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Post Box 17666, Al Ain, United Arab Emirates
Correspondence and offprint requests to: Martin Zenker MD, Institute of Human Genetics, Schwabachanlage 10, 91054 Erlangen, Germany. Email: mzenker{at}humgenet.uni-erlangen.de
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Abstract |
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Background. Pierson syndrome (OMIM 609049 [OMIM] ) is a severe congenital oculorenal disorder with early lethality. The condition is caused by mutations in the LAMB2 gene leading to complete loss of function of the gene product laminin ß2, an essential component of the glomerular and other basement membranes.
Methods. We present a non-consanguineous family with seven offspring affected by childhood-onset nephrotic syndrome progressing to end-stage renal failure and ocular abnormalities including cataracts, anterior chamber and iris abnormalities, and progressive blindness due to retinal detachment. The LAMB2 gene was analysed in this family by direct sequencing.
Results. The disorder turned out to segregate with compound heterozygosity for two novel LAMB2 mutations, 
V79 and Q1728X. Whereas the mutation Q1728X is predicted to confer complete loss of function, V79 probably represents a hypomorphic allele, thus explaining the substantially milder phenotype in this family.
Conclusion. This observation demonstrates that the phenotypic spectrum of LAMB2-associated disorders is broader than previously anticipated, and suggests that milder, non-lethal phenotypes may be associated with mutations retaining some residual function.
Keywords: autosomal recessive; blindness; laminin; nephrotic syndrome; Pierson syndrome
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Introduction |
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Pierson syndrome (OMIM 609049 [OMIM] ) is an autosomal recessive disorder comprising congenital nephrotic syndrome and a complex ocular maldevelopment [1]. Renal disease may already start prenatally, and early-onset renal failure, if not treated by renal replacement, is the cause of early death usually occurring in the newborn period. The most characteristic clinical feature in Pierson syndrome is microcoria, a fixed narrowing of the pupils due to a defect of the dilatator muscle, but ocular manifestations also include abnormalities of the lens (lenticonus posterior), cornea and retina [2]. LAMB2 mutations, mostly truncating ones, leading to lack of laminin ß2 were identified as the molecular basis of Pierson syndrome [3]. Patients who survive the newborn period due to renal replacement therapy are blind and may develop severe neurological deficits, consistent with the known expression of laminin ß2 in the nervous system (Wuehl et al., manuscript submitted).
Laminins are heterotrimeric molecules consisting of variable associations of each one 
-, ß- and 
-chain. Different laminin isoforms are present in virtually all basement membranes and play critical roles for attachment, differentiation and maintenance of functional integrity of adjacent cells [4]. The laminin ß2 chain has a restricted expression pattern that corresponds well to clinical findings in Pierson patients and lamb2 knockout mice in that laminin ß2 has been particularly found in the glomerular basement membrane, various ocular structures and the neuromuscular junctions [3,5,6].
The predominance of truncating LAMB2 mutations in patients with Pierson syndrome [3,7], and the association with a complete lack of protein expression [3] have raised the speculation that mutations retaining some residual protein function might be associated with different, probably milder phenotypes. We present a large non-consanguineous Pakistani family with a milder oculorenal syndrome due to compound heterozygosity for two novel LAMB2 mutations, suggesting previously unknown genotype–phenotype correlations in LAMB2-associated disorders.
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Subjects and methods |
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Clinical details
Clinical investigations were performed in the Department of Paediatrics of the University Al Ain, United Arab Emirates. Informed consent was obtained from all participating family members. Clinical findings in this family were reported previously [8]. Briefly, 7 of 14 children of a non-consanguineous Pakistani couple were found to have a similar condition comprising renal and ocular abnormalities. Three of the affected individuals were female and four were male (Figure 1). The onset of renal disease was insidious and could not be determined exactly. The earliest manifestation was asymptomatic proteinuria documented in a 4
-year-old boy (II-14). Clinical signs of nephrotic syndrome and end-stage renal failure occurred between the ages of 5–10 years. However, one male individual had sufficient kidney function until the age of 16 years (II-11), when the family was lost of follow-up. The oldest affected family member was on peritoneal dialysis from the age of 4 years and on haemodialysis from the age of 16 years. She was followed up until the age of 20 years (II-2). One girl died from renal disease at the age of 8 years (II-13). Renal histology findings were reported from two children, a 5-year-old girl with end stage renal disease (II-13) and a 4-year old-boy with asymptomatic proteinuria (II-14). Glomeruli in the mildly affected boy exhibited variable increase in cells and mesangial matrix, whereas the girl had extensive glomerulosclerosis with abnormalities of the glomerular basement membrane and foot process effacement on electron microscopy as well as tubulointerstitial changes. On immunohistochemistry the tissue samples from both children were positive for C3 deposits and one (II-14) also for IgG deposits, leading to the initial diagnosis of probable immuncomplex nephritis [8].
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Ocular problems paralleled or even preceded the renal symptoms. The ocular disorder was progressive in that all affected individuals were said to have had no signs of impaired vision in infancy and early childhood, but they all became blind around 2 years of age. Ophthalmological records are available only from the two youngest siblings. Retinal detachment was evident in both children and might have been the major cause of the progressive loss of vision. Additional ocular abnormalities reported in both children included variable cataracts, posterior synechiae, occlusio pupillae and anterior chamber abnormalities. The younger boy (II-14) had unilateral microphthalmia. Corneal and vitreous opacifications and iris atrophy were reported in one instance each. All affected individuals had a normal intelligence and no signs of any neuromuscular disease.
Nephrological and ophthalmological assessment of both parents revealed no abnormalities. There was no microalbuminuria in either of them.
Molecular analysis
Genomic DNA was extracted from peripheral blood samples by standard methods. All coding exons of the LAMB2 gene including their flanking intronic regions were analysed by direct bidirectional sequencing in one of the affected children, as described previously [3]. Subsequently, exons 2, 28 and 30 were analysed in all family members, except from II-2, II-5 and II-8, from whom no DNA samples were available. See Ensembl at http://www.ensembl.org/ for genomic location, MapView; gene, transcript and protein sequences and multiple protein alignment: human LAMB2 (ENSG00000172037).
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Results |
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Three novel sequence variations in the coding sequence of the LAMB2 gene were identified in the affected individual who had the full mutation screening: a 3 bp deletion in exon 2 (c.235-237delGTC) predicting an in frame deletion of the valine residue at position 79 (
V79), a C to T transition in exon 28 (c.4667C 
T) leading to an amino acid substitution A1556V, and another point mutation in exon 30 (c.5182C T) resulting in a premature termination codon (Q1728X). Investigations of the respective exons in all other family members available for genetic testing revealed that the combination of these three sequence variations were present in all affected family members but in none of the healthy siblings. The variations A1556V and Q1728X were found to be located on the same maternal allele (Figure 1). All three sequence changes have not been identified in our lab before in more than 100 individuals examined, to date. However, we did not have the opportunity to systematically screen an ethnically matched control group. |
Discussion |
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We demonstrate that the syndrome comprising glomerular kidney disease, cataracts, anterior chamber and iris abnormalities, and progressive loss of vision, perfectly segregated with compound heterozygosity for the mutations Q1728X and
V79 in this family. These findings strongly suggest that this disorder that was proposed to represent a separate clinical entity [8] is in fact a milder allelic variant of Pierson syndrome. Although the disorder observed in this family shares a similar pattern of organ involvement, it is clearly distinct from Pierson syndrome with respect to age of onset, course and histological presentation of renal disease, nature and course of ocular involvement and the absence of neurodevelopmental deficits. Renal manifestations of Pierson syndrome are characterized by prenatal or neonatal onset of nephrosis and renal failure associated with diffuse mesangial sclerosis. Renal disease in this family was originally classified as immuncomplex nephritis, although the evidence of an inflammatory/autoimmune pathogenesis remained elusive [8]. On re-evalution of the histological sections, the changes were judged to be rather compatible with focal and segmental glomerulosclerosis. The ocular manifestations in Pierson syndrome comprise abnormalities of cornea, iris, lens and retina, but the cause of profound vision impairment, which is apparently present at birth and non-progressive, has not been clarified. Progressive loss of vision in this family is obviously related to retinal detachment, which has not been described in Pierson syndrome before. This indicates that laminin ß2-containing laminins may be required for the proper attachment of the retina, similar to the role of laminin-5 at the dermo-epidermal junction [9].
We propose that this distinct phenotype is related to a particular genotype. In contrast to the vast majority of previously described and unpublished LAMB2 mutations found in Pierson syndrome patients in our lab [3,7], the paternally inherited mutation does not disrupt the reading frame. It deletes a single amino acid in a protein domain (domain VI) that is involved in protein interaction (polymerization) of laminins [10]. Val-79 and its neighbouring residues are highly conserved in laminin ß2 molecules from all other species available, as well as in human laminin ß1 (Figure 2), thus excluding as far as possible that V79 is a rare polymorphism even in the absence of a sufficiently large, ethnically matched control population. The structure of this domain is predicted to be stabilized mainly by intramolecular cystein bonds [10]. Thus, V79 may affect protein–protein interactions without substantial structural effects on the protein. Unfortunately, we did not have the opportunity to support our hypothesis by demonstrating a preserved laminin ß2 protein expression, because no biopsy material was left from either of the patients. In contrast, we assume that the maternally inherited allele represents a functional null allele (like classical Pierson syndrome mutations) based on the predicted premature termination codon at position 1728. The transcript is likely subjected to nonsense mediated mRNA decay. Even if a truncated protein is expressed, it has to be noted, that a previously described mutation located 77 bp downstream (c.5259insA) and leading to a stop at 1760 (of a total of 1798 amino acids) had been found to be associated with a complete lack of laminin ß2 expression [3]. In the presence of this truncating mutation, the variation A1556V on the same allele probably does not significantly contribute and may even represent a neutral polymorphism.
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The key findings of childhood-onset nephrosis, progressive renal failure and progressive loss of visual function were consistently present in all affected family members. However, there was some intrafamilial clinical variability, particularly regarding the age at end-stage renal failure ranging from 5 to more than 16 years. We cannot exclude that genetic modifiers unlinked to the LAMB2 locus may in part account for these intrafamilial differences. Variations in the other laminin chains (
5 and 1) constituting the major laminin isoform of the glomerular basement membrane or in laminin receptors (e.g. integrins) might be considered as potential modifiers. However, to date there is no experimental proof for the existence of genetic factors that can modulate the phenotype of LAMB2 defects, nor is there any evidence of triallelic inheritance with LAMB2 mutations. We conclude that LAMB2 has to be considered as the culprit of milder disorders including nephrosis and variable ocular anomalies. In order to avoid inappropriate splitting of clinical entities, we advocate the inclusion of this variant phenotype in the spectrum of Pierson syndrome which thus has to be expanded to milder non-lethal forms. Very recent findings suggest that LAMB2 mutations may even be associated with isolated renal disease [11].
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Acknowledgements |
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This work was supported by a grant from the German Research Foundation (DFG; ZE 524/3-1). We thank all family members for their cooperation.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 5. 7.06
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