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lama5

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Official Full Name
laminin, alpha 5
Background
Components of the extracellular matrix exert myriad effects on tissues throughout the body. In particular, the laminins, a family of heterotrimeric extracellular glycoproteins, affect tissue development and integrity in such diverse organs as the kidney, lung, skin, and nervous system. It is thought that laminins mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Laminins function as heterotrimeric complexes of alpha, beta, and gamma chains, with each chain type representing a different subfamily of proteins. The protein encoded by this gene belongs to the alpha subfamily of laminin chains and is a major component of basement membranes. Two transcript variants encoding different isoforms have been found for this gene, but the full-length nature of one of them has not been determined.
Synonyms
LAMA5; laminin, alpha 5; laminin subunit alpha-5; laminin alpha-5 chain; laminin-10 subunit alpha; laminin-11 subunit alpha; laminin-15 subunit alpha; KIAA1907; cb402; sb:cb402; im:7138247; wu:fb81a10; fra; fransen; unm m538

Recent Progress

The gene LAMA5 encodes laminin-α5, which is an essential component of the glomerular basement membrane. It may be associated with the disease named nephrotic syndrome (NS), which is a chronic kidney disease and characterized by considerable loss of protein in the urine causing hypoalbuminemia and edema. In general, about 10% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In about 25% of cases with SRNS, a causative mutation concerning LAMA5 can be detected in one of monogenic SRNS genes. Also, mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria.

There is also another connection with disease. About half of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome is a possible explanation of these findings. This links a LAMA5 variant with human renal disease and expands the spectrum of genes involved in glomerular pathologies accompanied by familial hematuria. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

It has been previously elucidated that mutations in the Fms-related tyrosine kinase 4 (FLT4) and forkhead box protein C2 (FOXC2) genes cause Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS), respectively, however, the mechanism underlying disease pathology remains unclear. Researchers identified four rare variants in the LAMA5 gene, in subjects carrying novel and known missense FLT4 mutations along with duplication and insertion in FOXC2. Significant lymphatic dysfunction was observed in both MD and LDS patients. In the MD patient, tortuous lymphatics in the dorsum of the foot were slowly enhanced. Dilated lymph collectors with disruption and lymph leakage were observed in the familial LDS case. Numerous tortuous lymph collectors were visualized along the entire length of affected lower limbs, and retrograde lymph flow was observed in the lymph collectors in the isolated LDS case. The finding of rare LAMA5 variants together with FLT4 and FOXC2 mutations suggested that these mutations may be co-responsible for these disorders and most likely interfere with the function of lymphatics.

Epithelial-mesenchymal transition (EMT) enhances the migration and invasion of cancer cells, and is regulated by various molecular mechanisms including extracellular matrix metalloproteinase (MMP) activity. Researchers have previously reported that transformation of epithelial Madin-Darby canine kidney (MDCK) cells with oncogenic H-Ras (21D1 cells) induces EMT, and significantly elevates MMP1 expression. It was shown that depletion of MMP1 lowered the ability of the cellular secretome (extracellular culture medium) to influence recipient cell behaviour. It was then revealed that LAMA5 can be a novel biological substrate of MMP1, which generates internal and C-terminal proteolytic fragments in 21D1 secretome (Fig.1). Furthermore, antibody-based inhibition of integrin αvβ3 on endothelial cells nullified the angiogenic capability of 21D1 secretome. Therefore, this could be a new VEGF-independent mechanism in which LAMA5 serves as substrate. This could be employed by oncogenic cells to promote tumour angiogenesis.

Fig. 1. LAMA5 is proteolytically fragmented by MMP1. (a) In silico prediction of MMP1 substrates. (b,c) Immuno-blot analysis of LAMA5 (b), and COL12A1 (c) expression in secretome samples. (Gopal et al, 2016)

References:

  1. Braun, D. A., Warejko, J. K., Ashraf, S., Tan, W., Daga, A., & Schneider, R., et al. (2018). Genetic variants in the lama5 gene in pediatric nephrotic syndrome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.
  2. Voskarides, K., Papagregoriou, G., Hadjipanagi, D., Petrou, I., Savva, I., & Elia, A., et al. (2018). Col4a5 and lama5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?. Bmc Nephrology, 19(1), 114.
  3. Sampaolo, S., Napolitano, F., Tirozzi, A., Reccia, M. G., Lombardi, L., & Farina, O., et al. (2017). Identification of the first dominant mutation of lama5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix. Journal of Medical Genetics.
  4. Bartolini, A., Cardaci, S., Lamba, S., Oddo, D., Marchiò, C., & Cassoni, P., et al. (2016). Bcam and lama5 mediate the recognition between tumor cells and the endothelium in the metastatic spreading of kras mutant colorectal cancer. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 22(19), 4923.
  5. Gopal, S. K., Greening, D. W., Zhu, H. J., Simpson, R. J., & Mathias, R. A. (2016). Transformed mdck cells secrete elevated mmp1 that generates lama5 fragments promoting endothelial cell angiogenesis. Scientific Reports, 6.