Alternative titles; symbols
HGNC Approved Gene Symbol: LAMB2
SNOMEDCT: 723449004;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:49,121,114-49,133,050 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Nephrotic syndrome, type 5, with or without ocular abnormalities | 614199 | Autosomal recessive | 3 |
| Pierson syndrome | 609049 | Autosomal recessive | 3 |
Laminin is a heterotrimeric extracellular matrix protein consisting of 3 chains: alpha, beta, and gamma (formerly A, B1, and B2). Several isoforms of each chain have been identified. Laminin has been shown to be important for cell differentiation, adhesion, migration, and neurite outgrowth. The laminin beta-2 chain, formerly S-laminin or the B1s chain, is a homolog of the laminin beta-1 (LAMB1; 150240) and beta-3 (LAMB3; 150310) chains and is located in synaptic basement membranes (Vuolteenaho et al., 1993). A part of the S-laminin chain has been shown to be selectively adhesive for motor neurons and inhibitory for neurite outgrowth.
Wewer et al. (1994) isolated overlapping cDNA clones that encode the full-length laminin beta-2 chain, formerly called the S chain. A 5,391-nucleotide open reading frame (ORF) encoded 1,797 amino acids. The human beta-2 chain was predicted to have all of the 7 structural domains typical of the beta chains of laminin, including the short cysteine-rich alpha region. The amino acid sequence of human beta-2 chain showed 86.1% sequence identity to the rat beta-2 chain, 50% identity to the human beta-1 chain, and 36.3% identity to the human beta-3 chain. Immunostaining showed that the beta-2 chain is localized to the smooth muscle basement membranes of arteries, whereas the homologous beta-1 chain is confined to the subendothelial basement membranes.
Durkin et al. (1996) determined the structural organization of the human and mouse genes that encode the laminin beta-2 chain. The human LAMB2 gene on 3p21 and the mouse Lamb2 gene on the distal region of mouse chromosome 9 show nearly identical organization. Both genes consist of 33 exons occupying approximately 12 kb of genomic DNA. Durkin et al. (1996) stated that these laminin beta-2 chain genes are the smallest laminin chain genes characterized to that time; the small size is due to the unusually small size of their introns. The organization of the laminin beta-2 chain gene is similar to that of the homologous human genes for the laminin beta-1 and beta-3 chains. Durkin et al. (1996) also identified an unusual nonconsensus 5-prime splice site in the first exon of the human LAMB2 gene. They suggested that inefficient splicing of this exon, which would not affect the primary sequence of the protein, may be involved in posttranscriptional regulation of laminin beta-2 chain gene expression.
Vuolteenaho et al. (1993) used a 2-kb cDNA clone of the S-laminin gene for Southern blot analysis of a panel of human-mouse somatic cell hybrids. The LAMS gene segregated concordantly with chromosome 3 and localized to 3p21-q21 in cell hybrids with chromosome 3 translocations.
Wewer et al. (1994) used the LAMB2 cDNA to assign the gene to 3p21 by isotopic in situ hybridization.
Bull et al. (2014) reported that the mouse Lamb2 gene maps to chromosome 9F3.
Nishimune et al. (2004) showed that laminin beta-2, a component of the synaptic cleft at the neuromuscular junction, binds directly to calcium channels that are required for neurotransmitter release from motor nerve terminals. This interaction leads to clustering of channels which in turn recruit other presynaptic components. Perturbation of this interaction in vivo results in disassembly of neurotransmitter release sites, resembling defects previously observed in an autoimmune neuromuscular disorder, Lambert-Eaton myasthenic syndrome (600003). Nishimune et al. (2004) concluded that their results identify an extracellular ligand of the voltage-gated calcium channel (see 601011) as well as a new laminin receptor, suggest a model for the development of nerve terminals, and provide clues to the pathogenesis of a synaptic disease.
Pierson Syndrome
Zenker et al. (2004) described Pierson syndrome (PIERS; 609049), an autosomal recessive entity comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular anomalies with microcoria as the leading clinical feature. In patients from 5 unrelated families with Pierson syndrome, Zenker et al. (2004) identified homozygous or compound heterozygous mutations of the LAMB2 gene (see 150325.0001-150325.0003). Most disease-associated alleles were truncating mutations. The respective LAMB2 mutations led to loss of laminin beta-2 expression in kidney and other tissues studied. In control samples, ocular laminin beta-2 expression was strongest in the intraocular muscles, corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in Pierson syndrome patients.
Nephrotic Syndrome, Type 5, with or without Ocular Abnormalities
In affected members of 2 unrelated families with congenital nephrotic syndrome (NPHS5; 614199), one of which also segregated minor ocular abnormalities, Hasselbacher et al. (2006) identified homozygosity or compound heterozygosity for missense mutations in the LAMB2 gene (150325.0006-150325.0008). The authors speculated that complete loss-of-function (e.g., truncating) mutations in the LAMB2 gene result in Pierson syndrome, whereas missense LAMB2 mutations result in congenital nephrotic syndrome with or without minor ocular abnormalities.
Maselli et al. (2009) reported a 20-year-old woman with congenital nephrotic syndrome and ocular abnormalities associated with compound heterozygous mutations in the LAMB2 gene (150325.0009 and 150325.0010). In the neonatal period, she had persistently constricted pupils and massive proteinuria. She received a renal transplant at age 15 months, which allowed unusually long survival. Motor milestones were delayed, and she had severe proximal limb muscle weakness. Detailed neuromuscular examination at age 7 years showed congenital myasthenic syndrome (CMS) with normal acetylcholinesterase (ACHE; 100740) activity. There was a decremental response of muscle action potential amplitude and a profound reduction of the quantal content of endplate potentials. Electron microscopy of the neuromuscular junction showed small axon terminal size and encasement of nerve endings by the Schwann cell, widening of the primary synaptic clefts with invasion of the synaptic space by processes of Schwann cells, moderate simplification of postsynaptic membranes, and decreased number of synaptic vesicles. Other clinical features included scoliosis, ptosis, impaired visual acuity, hypoplastic macular areas and poor foveal reflex, reactive pinpoint pupils, and limited extraocular movements. Cognition was normal. Maselli et al. (2009) noted that the muscular phenotype was similar to that observed in Lamb2-null mice (Noakes et al., 1995).
Mohney et al. (2011) described 11 (9 living) members of an extended consanguineous Old Order Mennonite family in which 11 (9 living) of 52 members had chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachment, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. All affected members had a novel homozygous mutation in the LAMB2 gene (H147R; 150325.0011).
S-laminin/laminin beta-2, a homolog of the much more widely distributed laminin B1/beta-1 chain (150240), is a major component of adult renal glomerular basement membrane (GBM). Immature GBM carries beta-1, which is replaced by beta-2 as development proceeds. Noakes et al. (1995) used homologous recombination to generate mice that carry a null mutation in the laminin beta-2 gene and documented defects in the maturation of their neuromuscular junctions. Focusing on kidneys in a separate study, Noakes et al. (1995) showed that the mice compensate for renal beta-2 deficiency by forming a GBM that contains laminin beta-1. The mutant GBM is structurally intact, but glomerular ultrafiltration is impaired. The defects resemble, in several respects, those seen in human minimal change nephrotic syndrome (MCNS), a glomerular disorder of unknown etiology that is most common in children. The mutant mice develop massive proteinuria. The GBM contains normal complements of several collagenous and noncollagenous glycoproteins. These results supported the idea that laminin beta chains are functionally distinct but assemble to form similar structures. Laminin beta-2-deficient mice may provide a model for human congenital or idiopathic nephrotic syndromes and can be excluded as the cause of Finnish congenital nephrotic syndrome (256300) because that disorder maps to chromosome 19. No glomerular phenotype has been noted in animal or humans with mutations in 2 other laminin genes: alpha-2 (dy/dy dystrophic mice) or gamma-2 (human junctional epidermolysis bullosa); see 226700.
In Lamb2-null mice, a model of Pierson syndrome, Jarad et al. (2006) observed ectopic deposition of several laminins and mislocalization of anionic sites in the GBM, suggesting that the Lamb2 -/- GBM is severely disorganized although ultrastructurally intact. Albuminuria was detectable shortly after birth in Lamb2-null mice and preceded podocyte foot process effacement and loss of slit diaphragms by at least 7 days. GBM permeability to ferritin was markedly elevated in Lamb2-null mice, even before widespread foot process effacement, and increased ferritin permeability was not seen in nephrotic Cd2ap (604241)-null mice, which have a primary podocyte defect. Jarad et al. (2006) concluded that the GBM serves as a barrier to protein in vivo and that the glomerular slit diaphragm alone is not sufficient to prevent the passage of albumin into the urinary space.
By whole-genome sequencing, Bull et al. (2014) identified a mutation in the Lamb2 gene that caused heavy proteinuria in mice in an N-ethyl-N-nitrosourea mutagenesis screen. The G-to-A transition in exon 5 of the mouse Lamb2 gene was predicted to result in a cys185-to-tyr (C185Y) substitution in the globular N-terminal domain important for Lamb2 trimer polymerization. Homozygous mutant mice, which the authors called nephertiti mice, appeared normal in survival, breeding, locomotor function, and behavior; however, they showed hypoproteinemia and hypoalbuminemia, raised cholesterol and triglycerides, and low body weight compared with wildtype. Urea and creatinine were not significantly elevated. Light microscopy of nephertiti kidneys detected protein casts within tubules and protein resorption droplets within tubular epithelium. The GBM was thickened, with basement membrane spikes. The subendothelial surface of the GBM remained smooth. There was moderate effacement of podocyte foot processes, but no IgG antibody accumulation. Bull et al. (2014) noted that the C185Y mutation lies N-terminal to the disulfide-bonded cysteines in the EGF-like repeats of Lamb2. They proposed that the relative preservation of podocyte structure in nephertiti mice, despite GBM thickening and nephrotic syndrome, may be due to a moderate effect of the mutation on Lamb2 protein folding.
Burgeson et al. (1994), a group of 14 leading researchers in the field of connective tissue proteins, adopted a new nomenclature for the laminins. They were numbered with arabic numerals in the order discovered. The previous A, B1, and B2 chains, and their isoforms, are alpha, beta, and gamma, respectively, followed by an arabic numeral to identify the isoform. For example, the first laminin identified from the Engelbreth-Holm-Swarm tumor (EHS) was designated laminin-1 with the chain composition alpha-1/beta-1/gamma-1. The genes encoding these 3 chains are LAMA1 (150320), LAMB1 (150240), and LAMC1 (150290).
In affected members of a consanguineous Lebanese family with a perinatal lethal form of Pierson syndrome (PIERS; 609049) described by Zenker et al. (2004), Zenker et al. (2004) identified a homozygous 1-bp deletion in the LAMB2 gene, 3015delG, resulting in a premature stop at codon 1150.
In affected members of a consanguineous Portuguese family with a lethal form of Pierson syndrome (PIERS; 609049) described by Glastre et al. (1990), Zenker et al. (2004) identified a homozygous arg246-to-trp (R246W) substitution in the LAMB2 gene at a highly conserved residue.
In a German child with Pierson syndrome (PIERS; 609049), Zenker et al. (2004) identified a homozygous 1-bp insertion in the LAMB2 gene, 5259insA, resulting in a premature stop at codon 1760.
Zenker et al. (2005) provided evidence that the original sibs with microcoria-congenital nephrosis syndrome (PIERS; 609049) reported by Pierson et al. (1963) were compound heterozygous for mutations in the LAMB2 gene. In the healthy mother and paternal aunt of the sibs, Zenker et al. (2005) identified 2 different heterozygous mutations in the LAMB2 gene: a 2067C-G transversion, resulting in a tyr689-to-ter (Y689X) substitution, and a 1122T-A transversion, resulting in a cys374-to-ter (C374X) substitution (150325.0005), respectively.
For discussion of the cys374-to-ter (C374X) mutation in the LAMB2 gene that was found in compound heterozygous state in sibs with microcoria-congenital nephrosis syndrome (PIERS; 609049) by Zenker et al. (2005), see 150325.0004.
In 2 affected sibs in a consanguineous Turkish family who had isolated congenital nephrotic syndrome with no ocular abnormalities (NPHS5; 614199), Hasselbacher et al. (2006) identified homozygosity for a 737G-A transition in exon 7 of the LAMB2 gene, resulting in an arg246-to-gln (R264Q) substitution.
In 2 affected sibs in a German Caucasian family who had isolated congenital nephrotic syndrome with mild ocular abnormalities, including myopia, fundus abnormality, and nystagmus (NPHS5; 614199), Hasselbacher et al. (2006) identified compound heterozygosity for 3 mutations in the LAMB2 gene: a 4140C-A transversion and a 4177C-T transition in exon 26 resulting in asn1380-to-lys (N1380K) and leu1393-to-phe (L1393F) mutations, respectively, located on the same, maternally inherited allele, and a 961T-C transition in exon 8 resulting in a cys321-to-arg (C321R) mutation on the paternally inherited allele.
For discussion of the cys321-to-arg (C321R) mutation in the LAMB2 gene that was found in compound heterozygous state in sibs with isolated congenital nephrotic syndrome with mild ocular abnormalities, including myopia, fundus abnormality, and nystagmus (NPHS5; 614199) by Hasselbacher et al. (2006), see 150325.0007.
In a 20-year-old woman with congenital nephrotic syndrome and ocular abnormalities (NPHS5; 614199), Maselli et al. (2009) identified compound heterozygosity for 2 mutations in the LAMB2 gene: a 1-bp deletion (1478delG) in exon 11 and a 1-bp deletion (4804delC; 150325.0010) in exon 29. Both mutations resulted in premature termination with no protein expression. Each mutation was inherited from an unaffected parent. The clinical history of the patient was unusual for the long survival due to successful kidney transplant at age 15 months. She had delayed motor development and proximal muscle weakness that was confirmed to be a congenital myasthenic syndrome later in childhood. There was a decremental response of muscle action potential amplitude and a profound reduction of the quantal content of endplate potentials. Electron microscopy of the neuromuscular junction showed small axon terminal size and encasement of nerve endings by the Schwann cell, widening of the primary synaptic clefts with invasion of the synaptic space by processes of Schwann cells, moderate simplification of postsynaptic membranes, and decreased number of synaptic vesicles. Other clinical features included scoliosis, ptosis, impaired visual acuity, hypoplastic macular areas and poor foveal reflex, reactive pinpoint pupils, and limited extraocular movements. Cognition was normal. Maselli et al. (2009) noted that the muscular phenotype was similar to that observed in Lamb2-null mice (Noakes et al., 1995).
For discussion of the 1-bp deletion in the LAMB2 gene (4804delC) that was found in compound heterozygous state in a patient with congenital nephrotic syndrome and ocular abnormalities (NPHS5; 614199) by Maselli et al. (2009), see 150325.0009.
Mohney et al. (2011) described an extended consanguineous Old Order Mennonite family with chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachment, but without microcoria or neurodevelopmental deficits (NPHS5; 614199). All affected members were homozygous for a 440A-G transition in the LAMB2 gene, resulting in a his145-to-arg (H147R) substitution. The mutation was located in a highly conserved site in the N-terminal domain VI of LAMB2. All obligate carriers in the family were heterozygous for the mutation, and normal sibs were either heterozygous or wildtype. Screening of 91 non-Mennonite control subjects did not identify the mutation, whereas screening of 96 Old Order Mennonite control samples revealed 2 heterozygotes, yielding a carrier frequency of 2.1%. The authors considered it to be a variant of Pierson syndrome (see 609049).
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