Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Gostyńska, Katarzyna B.; Yuen, Wing Yan; Pasmooij, Anna M. G.; Stellingsma, Cornelius; Pas, Hendri H.; Lemmink, Henny H.; Jonkman, Marcel F.

doi:10.1038/ejhg.2016.136

Cited by 18 publications

(16 citation statements)

References 18 publications

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“…8 , 9 , 10 , 11 Mutation or deletion of the LM332 α3 chain (LAMA3) can result in complete loss of LM332 in the basement membrane and affect HD formation, which eventually, can lead to junctional epidermolysis bullosa. 12 , 13 Taken together, those findings suggest that LAMA3 has a promising role in promoting LM332 synthesis and HD formation.…”

Section: Introductionmentioning

confidence: 79%

Adenovirus-Mediated LAMA3 Transduction Enhances Hemidesmosome Formation and Periodontal Reattachment during Wound Healing

Zhang

Zhen-xuan

et al. 2020

Molecular Therapy - Methods & Clinical Development

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A robust dento-epithelial junction prevents external pathogenic factors from entering connective tissue and could be crucial for periodontal reattachment after periodontal surgery. The junctional epithelium (JE) is attached to the tooth surface through the hemidesmosome (HD) and internal basal lamina, where the primary component is laminin-332. Destruction of the JE leads to the loss of periodontal attachment. Traditional treatments are effective in eliminating local inflammation of the gingiva; however, few directly promote periodontal reattachment and HD formation. Here, we designed a gene-therapy strategy using the adenovirus-mediated human laminin-332 α3 chain (LAMA3) gene (Ad-LAMA3) transduced into a human-immortalized epidermal cell line (HaCaT) to study the formation of HD in vitro . Ad-LAMA3 promoted early adhesion and fast migration of HaCaT cells and increased expression of LAMA3 and type XVII collagen (BP180) significantly. Furthermore, HaCaT cells could facilitate formation of mature HDs after LAMA3 overexpression. In vivo experiments demonstrated that the JE transduced with Ad-LAMA3 could increase expression of LAMA3 and BP180 and “biological sealing” between the tooth and gingival epithelium. These results suggested that adenovirus-mediated LAMA3 transduction is a novel therapeutic strategy that promotes the stability and integration of the JE around the tooth during wound healing.

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Section: Introductionmentioning

confidence: 79%

Adenovirus-Mediated LAMA3 Transduction Enhances Hemidesmosome Formation and Periodontal Reattachment during Wound Healing

Zhang

Zhen-xuan

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Many recent studies have indicated that adhesion and extracellular matrix proteins contribute to the progression of a variety of solid tumors, including pancreatic cancer 20–22 . LM-332, which is encoded by LAMA3, LAMB3, and LAMC2, is related to tumor invasiveness in various types of malignant tumors 23–25 . LAMB3 is a potential biomarker of cancer invasion and metastasis that is involved in the focal adhesion pathway, but a role for LAMB3 in pancreatic cancer has not been investigated previously 26,27 .…”

Section: Discussionmentioning

confidence: 99%

LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway

et al. 2019

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The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is partially attributed to the invasive and metastatic behavior of this disease. Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, an extracellular matrix protein secreted by cultured human keratinocytes. In addition, LAMB3 is involved in the invasive and metastatic abilities of some types of cancer, including colon, pancreas, lung, cervix, stomach, and prostate cancer, but the role and mechanism of LAMB3 in PDAC have not been previously determined. Herein, we tentatively investigated the role of LAMB3 in the malignant biological behavior of PDAC. In this study, we demonstrated that LAMB3 is upregulated in PDAC. Inhibition of LAMB3 abrogated the tumorigenic outcomes of PI3K/Akt signaling pathway activation, including those involving cell cycle arrest, cell apoptosis, proliferation, invasion and migration in vitro, and tumor growth and liver metastasis in vivo. Our results showed that LAMB3 could mediate cell cycle arrest and apoptosis in PDAC cells and alter the proliferative, invasive, and metastatic behaviors of PDAC by regulating the PI3K/Akt signaling pathway. LAMB3 may be a novel therapeutic target for the treatment of PDAC in the future.

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“…The early lethal JEB generalized severe subtype results from absent LM332, while generalized intermediate (JEB-GI) or localized JEB forms associate with variably reduced LM332 amounts. In addition, JEB-related non-blistering conditions with specific tissue manifestations result from dominant haploinsufficiency or from partial loss-of-function that spares the amount and coiled coil domain of the heterotrimer [3,[11][12][13]. JEB-GI can also be due to genetic defects in COL17A1 encoding collagen XVII [14].…”

Section: Introductionmentioning

confidence: 99%

Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function

Fortugno

Condorelli

Dellambra

et al. 2020

IJMS

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Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a β3 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to γ2 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient.

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Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Cited by 18 publications

References 18 publications

Adenovirus-Mediated LAMA3 Transduction Enhances Hemidesmosome Formation and Periodontal Reattachment during Wound Healing

Adenovirus-Mediated LAMA3 Transduction Enhances Hemidesmosome Formation and Periodontal Reattachment during Wound Healing

LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway

Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function

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