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

Mutations in the laminin β2 (LAMB2) gene are associated with Pierson syndrome [1]. In 2004, this rare autosomal recessive disorder was first described in patients suffering from congenital nephrotic syndrome (i.e., presenting before the age of 3 months) with rapid progression to end-stage renal disease (ESRD), combined with distinct ocular malformations and neurodevelopmental deficits. Ocular manifestations included microcoria, abnormal lens shape with cataracts, and retinal abnormalities [1, 2]. In the last decade, milder phenotypes associated with various LAMB2 mutations have been reported [2‐6]. The LAMB2 gene is located on chromosome 3 and encodes the laminin β2 protein belonging to the laminin family of extracellular matrix glycoproteins, which are the major non-collagenous constituents of basement membranes. They have been implicated in a wide variety of biological processes [7]. Laminins represent a group of cross-shaped heterotrimeric proteins consisting of α, β, and γ subunits joined together to form a 3D-coiled structure [4, 8]. The human LAMB2 gene is composed of 32 densely packed exons and encodes a protein of 1798 amino acids [4, 7, 8]. The laminin β2 protein is the major laminin component of the glomerular basement membrane and is also involved in ocular and neuromuscular synapse development [2, 7]. It has been postulated that the severe phenotype, as originally described by Pierson, is associated with truncating LAMB2 mutations leading to a complete loss of laminin β2 expression and that milder phenotypes reflect mutations with residual laminin β2 function [3, 4]. In this report, we describe a novel mutation in the LAMB2 gene and its associated phenotype.

This report describes a novel mutation in exon 8 of LAMB2, the gene associated with Pierson syndrome and its milder variants [1, 2, 4]. The reported c.970T>C p.(Cys324Arg) variant has previously not been described in patients and was absent in >60.000 controls (http://​exac.​broadinstitute.​org). The cysteine residue on position 324 is strongly conserved and lies within the first EGF-like module of the laminin β2 protein. This module contains eight conserved cysteine residues, which form disulfide bonds in order to achieve a correct 3D structure. The cysteine residue on position 324 is involved in the fourth disulfide bond in the EGF-like module (Fig. 3). Mutation of a nearby cysteine in the LAMB2 gene (position 321; compound heterozygous with a Leu1393Phe and Asn1380Lys mutation) is a known pathogenic mutation and has been shown to be involved in the third disulfide bond of the domain [3, 4]. Reported patients presented with congenital nephrotic syndrome and ocular abnormalities consisting of nystagmus, myopia, strabismus, and hypopigmented retina. Additionally, a p.(Cys310Arg) mutation was found by mutational screening of a study population of steroid-resistant nephrotic syndrome [10], underscoring the importance of cysteines in this protein domain. Mutations in the LAMB2 gene described thus far comprise missense, nonsense and splice site mutations, as well as small deletions and insertions, found either as homozygous or compound heterozygous sequence changes [4]. Genotype-phenotype correlation studies have revealed a significantly earlier manifestation (nephrosis <3 months of age) and worse prognosis (ESRD <1 year of age) of the renal phenotype in truncating LAMB2 mutations (functional null alleles), compared to missense mutations (possibly hypomorphic alleles) [2, 4]. Regarding the ocular manifestations, almost all patients harboring bi-allelic nonsense or frameshift mutations exhibited microcoria in association with variable ocular abnormalities [9], while patients without microcoria showed variable mutation types [4]. With regard to the neurological phenotype, a previous genotype-phenotype study found 22 of 42 patients with LAMB2 mutations who underwent neurological evaluation, to have neurodevelopmental deficits consisting of significant hypotonia/muscle weakness/myasthenia, significant motor delay and suspected or proven cognitive defects. These neurodevelopmental deficits were not clearly associated with a specific mutation type [4]. These observations show that although there is evidence for a genotype-phenotype correlation with respect to the renal and ocular phenotype in LAMB2 mutations, the neurodevelopmental manifestations remain clinically variable and thus unpredictable.

The herein described c.970T>C p.(Cys324Arg) variant is considered a pathogenic missense mutation which probably results in disturbed formation of the fourth disulfide bond and hence disturbed 3D structural conformation of the laminin β2 protein. The aberrant protein presumably contains residual function (hypomorphic allele) and hence leads to a milder phenotype compared to the classic Pierson Syndrome [2].

The currently reported mutation corresponds to a phenotype with therapy-resistant nephrotic syndrome at the age of 18 months, leading to progressive renal failure, with end-stage renal failure within 4–5 years, accompanied by ocular abnormalities consisting of high myopia, microcoria, thinning of the retina with absence of the foveal reflex (n = 1) and optic nerve abnormalities (n = 1).

This report presents the variability of the renal, ocular, and neurological phenotypes associated with LAMB2 mutations [4, 11], and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome.