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lamb3

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Official Full Name
laminin, beta 3
Background
The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene.
Synonyms
LAMB3; laminin, beta 3; LAM5; LAMNB1; FLJ99565; BM600-125KDA; laminin subunit beta-3; nicein-125kDa; kalinin B1 chain; laminin B1k chain; OTTHUMP00000034555; OTTHUMP00000034640; laminin S B3 chain; nicein subunit beta; laminin-5 subunit beta; kalinin subunit beta; laminin, beta 3 (nicein (125kD), kalinin (140kD), BM600 (125kD)) , LAMNB1; BM600 125kDa; kalinin 140kDa; nicein 125kDa; kalinin-140kDa; epiligrin subunit bata; laminin, beta 3 (nicein (125kD), kalinin (140kD), BM600 (125kD))

Recent Progress

Amelogenesis imperfecta (AI), which is a group of inherited diseases affecting the quality and quantity of dental enamel, can be either isolated or part of a larger syndrome. ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. Furthermore, when both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB), while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. Through investigation into two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI, which is characterized by generalized severe enamel hypoplasia with deep linear grooves and pits), researchers identified novel heterozygous mutations in the last exon of LAMB3 that may have truncated the protein. This indicated that enamel formation is particularly sensitive to defects in hemi-desmosome and that syndromic and non-syndromic forms of AI can be etiologically related.

In another study, researchers studied three Chinese families with hypoplastic autosomal-dominant AI. Disease-causing mutations were identified and segregated with the enamel defects in three families: a insertion mutation in the exon 7 of ENAM in Family 1, a single-base deletion mutation in the exon 5 of ENAM in Family 2, and a LAMB3 nonsense mutation in the last exon in Family 3. These findings suggested that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients, extending the mutation spectrum of both genes and may be used for mutation screening of AI in the Chinese population (Fig.1).

Fig. 1. The electron-density distribution of the predicted C-terminus of the wild-type and mutant LAMB3 protein. The predicted C-terminal end is shown by electrostatic potential surfaces, which are differed extensively between the wild-type and mutant LAMB3 protein (blue represents positive potential; red, negative; white, neutral). (Wang et al, 2015)

Moreover, researchers have identified a low-frequency coding variant rs2076349 in the LAMB3 gene with strong association with morbid obesity and thereby risk of type 2 diabetes. Researcher selected 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis, rs2076349 showed strong association with obesity. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology. LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. These findings identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene.

While trying to identify novel gene interactions in KRAS-mutant cancer cells, researchers discovered miR-1298, a novel miRNA that inhibited the growth of KRAS-driven cells both in vitro and in vivo. Furthermore, the LAMB3 were determined as functional targets of miR-1298. Silencing of LAMB3 recapitulated the synthetic lethal effects of miR-1298 expression in KRAS-driven cancer cells, while co-expression of both proteins was critical to arrest miR-1298-induced cell death. Expression of LAMB3 was upregulated by mutant KRAS. In clinical specimens, elevated LAMB3 expression was correlated with poorer survival in lung cancer patients with an oncogenic KRAS gene signature, suggesting a novel candidate biomarker in this disease setting.

To identify the key regulatory genes involved in lung cancer, researchers performed a combination of analyses to compare gene transcription profiles in 3 monoclonal cell strains with high, medium or low metastatic abilities. Gene array and bioinformatics analyses implied that LAMB3 and ITGB1 were key genes involved in lung cancer. Knockdown of these genes suppressed human lung cancer cell invasion and metastasis in vitro and in vivo. Clinical sample analyses indicated that LAMB3 and ITGB1 protein expression levels were higher in lung cancer patients compared to non-cancerous adjacent tissues, and could be correlated with lymphatic metastasis. These findings suggested that LAMB3 and ITGB1 played important roles in the occurrence and metastasis of lung cancer.

References:

  1. Kim, J. W., Seymen, F., Lee, K. E., Ko, J., Yildirim, M., & Tuna, E. B., et al. (2013). Lamb3 mutations causing autosomal-dominant amelogenesis imperfecta. Journal of Dental Research, 92(10), 899-904.
  2. Lee, K. E., Ko, J., Le, C. G., Shin, T. J., Hyun, H. K., & Lee, S. H., et al. (2015). Novel lamb3 mutations cause non-syndromic amelogenesis imperfecta with variable expressivity. Clinical Genetics, 87(1), 90–92.
  3. Wang, X., Zhao, Y., Yang, Y., & Qin, M. (2015). Novel enam and lamb3 mutations in chinese families with hypoplastic amelogenesis imperfecta. Plos One, 10(3), e0116514.
  4. Jiao, H., Kulytã, A., NãSlund, E., Thorell, A., Gerdhem, P., & Kere, J., et al. (2016). Whole-exome sequencing suggests lamb3 as a susceptibility gene for morbid obesity. Diabetes, 65(10), 2980-2989.
  5. Zhou, Y., Dang, J., Chang, K. Y., Yau, E., Aza-Blanc, P., & Moscat, J., et al. (2016). Mir-1298 inhibits mutant kras-driven tumor growth by repressing fak and lamb3. Cancer Research, 76(19), 5777.
  6. Wang, X. M., Li, J., Yan, M. X., Liu, L., Jia, D. S., & Geng, Q., et al. (2013). Integrative analyses identify osteopontin, lamb3 and itgb1 as critical pro-metastatic genes for lung cancer. PLOS ONE, 8(2), e55714.