LAMB2

Official Full Name

laminin subunit beta 2

Organism

Homo sapiens

GeneID

3913

Background

Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the beta chain isoform laminin, beta 2. The beta 2 chain contains the 7 structural domains typical of beta chains of laminin, including the short alpha region. However, unlike beta 1 chain, beta 2 has a more restricted tissue distribution. It is enriched in the basement membrane of muscles at the neuromuscular junctions, kidney glomerulus and vascular smooth muscle. Transgenic mice in which the beta 2 chain gene was inactivated by homologous recombination, showed defects in the maturation of neuromuscular junctions and impairment of glomerular filtration. Alternative splicing involving a non consensus 5' splice site (gc) in the 5' UTR of this gene has been reported. It was suggested that inefficient splicing of this first intron, which does not change the protein sequence, results in a greater abundance of the unspliced form of the transcript than the spliced form. The full-length nature of the spliced transcript is not known. [provided by RefSeq, Aug 2011]

Synonyms

LAMS; NPHS5; PIERS;

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Detailed Information

Recent Progress

Mutations of the LAMB2 gene mainly cause Pierson syndrome, which is characterized by congenital nephrotic syndrome (CNS) and the most prominent clinical feature is complex ocular involvements with microcoria. However, the phenotypic spectrum of LAMB2-associated disorders could be broader, with isolated congenital or infantile nephrotic syndrome which can also be seen. In order to explore the phenotypes of different LAMB2 mutations in China, LAMB2 mutations were analyzed in three Chinese childhood steroid-resistant nephrotic syndrome cases, two of them with ocular abnormalities. LAMB2 mutations were confirmed in all three, two presented with Pierson syndrome, while one presented with isolated infantile steroid-resistant nephrotic syndrome. These cases are to suggest that the phenotypes caused by LAMB2 mutation were variable, mainly Pierson syndrome, as well as isolated nephrotic syndrome without ocular involvement.

A case of neonatal Pierson syndrome in conjunction with complex cyanotic cardiac disease, in which a novel homozygous mutation in the LAMB2 gene, was also detected. The clinical association of Pierson syndrome with heart manifestation is a novel finding, which was reported for the first time. Researchers also reported a novel homozygous nonsense mutation in the LAMB2 gene, associated with a severe phenotype presentation. They described a male infant born from consanguineous parents. The given case presented at birth with bilateral microcoria, severe hypotonia, respiratory distress, and congenital nephrotic syndrome associated with anuria and severe renal failure requiring peritoneal dialysis. Genetic analysis revealed a homozygous nonsense mutation at position c.2890C>T, causing a premature stop codon in LAMB2 gene. This novel nonsense homozygous mutation in LAMB2 gene caused the severe neonatal presentation of Pierson syndrome. This new mutation broadens the genotype–phenotype spectrum of this rare disease and confirms that truncating mutations could be associated with severe clinical features.

Another report described a novel mutation of LAMB2 in two female siblings. The c.970T>C mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the LAMB2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is associated with later-onset therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria and diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings. This report expanded the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations (Fig.1).

Fig. 1. Schematic drawing of the functional domains of the human laminin β2 chain. (Falix et al, 2017)

In order to improve understanding about the steroid resistance nephrotic syndrome (SRNS) and Pierson syndrome, the case of a male patient of steroid resistant nephrotic syndrome with LAMB2 mutations but without the ocular abnormality was investigated. Results revealed focal segmental glomerular sclerosis (FSGS) and no ophthalmic abnormity, along with massive proteinuria and hypoproteinemia. The mutations of LAMB2 were found of 21 genes for congenital nephrotic syndrome and confirmed by sequencing. This meant that the novel compound heterozygous LAMB2 mutation was seen in the case of SRNS. Gene mutations should be taken into considering to those patients with steroid resistant nephritic syndrome or nephrotic range proteinuria regardless of accompanying extrarenal abnormalities.

References:

Zhang, H., Cui, J., Wang, F., Xiao, H., Ding, J., & Yao, Y. (2017). Lamb2 mutation with different phenotypes in china. Clinical Nephrology, 87 (2017)(1), 33.
Zemrani, B., Cachat, F., Bonny, O., Giannoni, E., Durig, J., & Fellmann, F., et al. (2016). A novel lamb2 gene mutation associated with a severe phenotype in a neonate with pierson syndrome. European Journal of Medical Research, 21(1), 19.
Falix, F. A., Bennebroek, C. A., Van, d. Z. B., Lapid-Gortzak, R., Florquin, S., & Oosterveld, M. J. (2017). A novel mutation of laminin β2 (lamb2)in two siblings with renal failure:. European Journal of Pediatrics, 176(4), 515-519.
Yang, F. J., Zhou, J. H., & Qiu, L. R. (2015). Steroid-resistant nephrotic syndromeassociated with lamb2 gene mutation. Journal of Developmental Medicine.
Parappil, H., Ali, R., Masud, F., Pai, A., Nahavandi, N., & Rolfs, A., et al. (2015). Pierson syndrome: a case report with a neonatal cardiac association based on a novel mutation in the lamb2 gene. Journal of Clinical Neonatology.

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