A novel mutation of laminin β2 (LAMB2) in two siblings with renal failure

Abstract

This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin β2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings.

Conclusion: this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.

Keywords: LAMB2; Nephrotic syndrome; Ocular abnormalities; Pierson syndrome.

Fig. 1

Histopathological findings after nephrectomy in case 2. a Representative overview of the renal tissue showing extensive chronic damage with globally sclerotic glomeruli, interstitial fibrosis, inflammation, and tubular atrophy (PAS-diastase staining, ×10). b One glomerulus with segmental sclerosis (PAS-diastase staining, ×20). c One glomerulus with florid proliferation of parietal epithelial cells (PAS-diastase staining, ×20). d Electron microscopy showing irregular glomerular basement membrane and effacement of the podocytes

Fig. 2

Ophthalmological findings in case 2: fundusphotography and cross-sectional (B-scan) detailed imaging of the macula, performed with spectral domain (SD)-OCT (Topcon 3D OCT-2000 device) a Left eye in case 2: the fundus shows diffuse tessellation of the retina, a mild waxy appearance of the optic nerve surrounded by a large scleral crescent. The macular reflex is absent, retinal vessels are prominently stretched. b Optic coherence tomography (OCT) of a healthy child: normal appearance of fovea, retinal contour, and thickness. OCT uses reflected light to form a cross-sectional image of the retina by automatic analysis of the reflective properties of retinal tissue. c OCT of the left eye of case 2: in the central area of the macula, a normal foveal contour is absent and retinal thickness is reduced (214 versus 245 μm average for age of 6 years). The retina shows a diffuse irregular contour. The scan is of limited quality due to poor cooperation, therefore individual analysis of retinal layers could not be performed

Fig. 3

Schematic drawing of the functional domains of the human laminin β2 chain. The red asterisk indicates the position of the c.970T>C p.(Cys324Arg) mutation found in our patients. The first EGF-like module is depicted on the right; the blue line represents the amino acid sequence with only the highly conserved cysteine residues shown in yellow. The pink connecting lines indicate disulfide bonds. The light blue asterisks in the right panel indicates the position of the mutated seventh cysteine residue, which is replaced by arginine; p.(Cys324Arg)