Disease relevance of LAMB3

• The blistering disorder, lethal junctional epidermolysis bullosa (JEB), can result from mutations in the LAMB3 gene, which encodes laminin 5 beta3 (beta3) [1].
• Laminin 5, a candidate gene/protein system for mutations in the junctional forms of epidermolysis bullosa (JEB), consists of three polypeptides encoded by the LAMA3, LAMB3, and LAMC2 genes [2].
• In the recessive dystrophic epidermolysis bullosa patients, transcripts containing in-frame skipping of exon 19 of COL7A1 in the cDNA were detected, and in the junctional epidermolysis bullosa patients transcripts with in-frame skipping of exon 17 of LAMB3 were identified [3].
• RESULTS: The frequencies of loss of expression for the LAMA3, LAMB3, and LAMC2 genes in six prostate cancer cell lines were 83, 67, and 50%, respectively, whereas the methylation frequencies were 83, 67, and 33%, respectively [4].
• Methylation frequencies of LAMA3, LAMB3, and LAMC2 genes in 20 breast cancer cell lines were 40, 5, and 15%, respectively [5].

High impact information on LAMB3

• Previously, in different JEB phenotypes, mutations have been found in the three genes for the anchoring filament component laminin 5 (LAMA3, LAMB3, and LAMC2) and in the gene for the hemidesmosome-associated integrin beta 4 subunit [6].
• In vivo restoration of laminin 5 beta 3 expression and function in junctional epidermolysis bullosa [1].
• In contrast, single heterozygotes carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathological skin phenotype [7].
• Thus, the results suggested that reduction to homozygosity of the 1q region containing the maternal LAMB3 mutation caused the H-JEB phenotype [8].
• In this study, we describe a unique patient with H-JEB, who was homozygous for a nonsense mutation, Q243X, in the LAMB3 gene on chromosome 1 and who had normal karyotype 46,XY [8].

Biological context of LAMB3

• In this study, primer pairs for the amplification of the complete cDNA as well as 22 exons of the LAMB3 gene encoding the entire beta 3 chain of laminin 5, were established [2].
• In this study, we describe a patient homozygous for a novel nonsense mutation Q936X in exon 19 of LAMB3, which has been mapped to chromosome 1q32 [9].
• In one case, a homozygous frameshift mutation in LAMB3 was associated to illegitimate splicing leading to non-H JEB [10].
• Genotype analysis using 28 microsatellite markers spanning chromosome 1 revealed that the patient had maternal primary heterodisomy, as well as meroisodisomy within two regions of chromosome 1, one on 1p and the other one on 1q, the latter region containing the maternal LAMB3 mutation [9].
• Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa [8].

Anatomical context of LAMB3

• We have isolated epidermal keratinocytes from a patient presenting with a lethal form of junctional epidermolysis bullosa characterized by a homozygous mutation of the LAMB3 gene, which led to complete absence of the beta3 polypeptide [11].
• Laminin-5 (LN5) anchors epithelial cells to the underlying basement membrane, and it is encoded by three distinct genes: LAMA3, LAMB3, and LAMC2 [12].
• Both fetuses were found to be heterozygous carriers of the W610X mutation together with a normal LAMB3 allele, indicating that they were phenotypically unaffected [13].
• Mutations in the genes (LAMA3, LAMB3, and LAMC2) encoding the subunit polypeptides of the cutaneous basement membrane zone protein laminin 5 have been reported in different forms of junctional epidermolysis bullosa (JEB), an inherited blistering skin disease [14].
• METHODS: Two infants, both homozygous for the Herlitz mutation R635X in the LAMB3 gene, who had refractory anemia and hypoproteinemia as a result of a continuous loss of body fluids through multiple large erosions, were treated with artificial skin bioequivalents [15].

Regulatory relationships of LAMB3

• Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration [16].

Other interactions of LAMB3

• Collectively, five mutations appeared to be frequent in laminin-5 JEB patients: R635X, 29insC, E210K, W143X in LAMB3 and R95X in LAMC2 [10].
• Comparison of the LAMB3 gene structure with the previously characterized LAMB1 gene revealed that LAMB3 was considerably more compact [17].
• PTGFR, and LAMB3 localized at both ends of the HSA1 region were assigned to SSC6 and SSC9, respectively, which is consistent with regional correspondence reported earlier [18].
• The index patient was compound heterozygous for the COL17A1 mutations L855X and R1226X and was heterozygous for the LAMB3 mutation R635X [7].
• Reverse transcriptase polymerase chain reaction analysis suggested skipping of exon 19 in LAMB3 mRNA produced from the allele with 2702-29del94 and impaired stability of the aberrant mRNA transcribed from the second allele with the 1977-2A-->G mutation [19].

Analytical, diagnostic and therapeutic context of LAMB3

• The amplified sequences were used to study sequence variations of the LAMB3 gene in patients with JEB and unrelated individuals using heteroduplex analysis [2].
• The remaining alleles were subjected to mutation screening by PCR amplification of individual exons of LAMB3 and LAMC2, followed by heteroduplex analysis and nucleotide sequencing [20].
• Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence [21].
• Polymerase chain reaction (PCR) amplification of exon 10 and parts of the flanking introns of the gene encoding the beta 3 chain of laminin 5 (LAMB3) and subsequent analysis by agarose gel electrophoresis showed a more slowly migrating band in the affected fetus compared with the normal control [22].
• Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells [23].

References