Alternative titles; symbols
HGNC Approved Gene Symbol: LAMA3
SNOMEDCT: 722675000;
Cytogenetic location: 18q11.2 Genomic coordinates (GRCh38) : 18:23,689,453-23,955,066 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q11.2 | Epidermolysis bullosa, junctional 2A, intermediate | 619783 | Autosomal recessive | 3 |
| Epidermolysis bullosa, junctional 2B, severe | 619784 | Autosomal recessive | 3 | |
| Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous | 245660 | Autosomal recessive | 3 |
Laminin-5 (LAM5) is an isoform within the laminin family of proteins that is composed of 3 distinct polypeptides, the alpha-3, beta-3 (LAMB3; 150310), and gamma-2 (LAMC2; 150292) chains, according to the nomenclature of Burgeson et al. (1994). Laminin-5 has also been referred to as nicein, kalinin, and epiligrin (Ryan et al., 1994).
Ryan et al. (1994) isolated cDNA clones encoding the 170-kD chain of epiligrin and a genomic clone encoding the LAMA3 gene. Analysis of multiple cDNA clones revealed 2 distinct transcripts.
Vidal et al. (1995) isolated a cDNA clone corresponding to the LAMA3 gene. The authors also reported the identity of the alpha chains of laminin-5, and provided evidence that LAMA3 transcripts are distinct from the laminin-6 alpha chain mRNA. In epithelial basement membranes, laminin-5 and laminin-6 form a complex that functions as a cell adhesion ligand for integrins, and it had been suggested that laminins 5 and 6 may share the same alpha chain.
By fluorescence in situ hybridization, Ryan et al. (1994) mapped the LAMA3 gene to chromosome 18q11.2, a locus distinct from the LAMA1 gene (150320), which is located on 18p11.3.
Taniuchi et al. (1999) described a 61-year-old patient with acquired circulating autoantibodies to epiligrin (laminin-5) and cicatricial pemphigoid associated with advanced gastric carcinoma. Immunofluorescence microscopy and immunoprecipitation studies demonstrated that the gastric carcinoma cells in this patient produced laminin-5, and that the patient's serum contained autoantibodies directed against laminin-5. The blistering symptoms and the titer of antibasement membrane zone antibodies coordinately changed with the resection and subsequent relapse of the gastric cancer. Taniuchi et al. (1999) concluded that cicatricial pemphigoid in this patient was a paraneoplastic disorder.
Intermediate Junctional Epidermolysis Bullosa 2A
Nakano et al. (2002) identified mutations in the LAMA3 gene in patients with non-Herlitz junctional epidermolysis bullosa (JEB2A; 619783); see, e.g., 600805.0003.
Severe Junctional Epidermolysis Bullosa 2B
In a boy with the lethal Herlitz form of junctional epidermolysis bullosa (JEB2B; 619784), Kivirikko et al. (1995) identified a homozygous nonsense mutation in the LAMA3 gene (R650X; 600805.0002). The infant was born of consanguineous Asian parents and died in early infancy.
McGrath et al. (1995) identified a homozygous R650X mutation in a child with Herlitz JEB who was born of consanguineous Pakistani parents. The patient presented at birth with extensive blisters and erosions. Electron microscopy of the skin revealed scanty, rudimentary hemidesmosome-anchoring filament complexes and tissue separation within the lamina lucida. Immunofluorescence staining of the basement membrane zone with an anti-laminin-5 antibody revealed absent labeling. Both unaffected parents were heterozygous mutation carriers. Fetal DNA extracted from a chorionic villus biopsy obtained at 10 weeks' gestation in a subsequent pregnancy showed that the fetus was not affected.
Laryngoonychocutaneous Junctional Epidermolysis Bullosa 2C
Laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C; 245660), also known as laryngoonychocutaneous or Shabbir syndrome (LOCS), is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. McLean et al. (2003) localized the gene for LOCS to a 2-Mb region on chromosome 18q11.2 (lod = 19.8 at theta = 0), which includes the LAMA3 gene. The authors determined that 3 distinct isoforms of the LAMA3 gene product were expressed due to differential splicing, which they designated laminin alpha-3a, alpha-3b1, and alpha-3b2. A causative LAMA3 mutation was identified in 15 consanguineous Punjabi LOCS families, consisting of a frameshift mutation (151insG; 600805.0004) predicting a stop codon in an exon that is specific to LAMA3. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOCS may be caused by dysfunction of keratinocyte-mesenchymal communication. The authors hypothesized that the laminin alpha-3a N-terminal domain may be a key regulator of the granulation tissue response. Fine et al. (2008) noted that Shabbir syndrome is considered to be a variant of JEB.
Figueira et al. (2007) described a 7-year-old Caucasian boy with overlapping features of JEB and LOCS. They identified compound heterozygosity for mutations in the LAMA3 gene: a paternally inherited splice site mutation at the donor site of intron 35 (c.4651+1G-A; 600805.0006) and a maternally inherited missense mutation (I17N; 600805.0009) in the laminin alpha-3a isoform. Figueira et al. (2007) noted that the case was unique in having several features of LOCS (eyelid and laryngeal granulation tissue) and mutations in both the laminin alpha-3 and laminin alpha-3a isoforms, providing evidence that LOC is a variant of JEB.
In 2 Iranian sibs with LOCS, Barzegar et al. (2013) identified homozygosity for a nonsense mutation (G57X; 600805.0007) in the LAMA3 gene. The variation affects only the laminin alpha-3a transcript. Two unaffected sibs as well as both parents were heterozygous for this mutation. The mutation occurred 18 basepairs downstream from the 151insG mutation (600805.0004) described by McLean et al. (2003) in the original Punjab families.
In a proband and brother with a phenotype most closely resembling LOCS, Wang et al. (2022) identified a homozygous nonsense mutation in the LAMA3 gene (W16X; 600805.0008). The W16X variant is located in exon 1 of the laminin alpha-3a (LAMA3A) transcript, specific to LAMA3A and corresponding to exon 39 of the full-length LAMA3 gene.
Ryan et al. (1999) observed that mice with a targeted disruption of the mouse Lama3 gene had profound epithelial abnormalities resulting in neonatal lethality. The Lama3-null animals developed junctional blisters in the skin caused by a separation at the dermal-epidermal junction, similar to that observed in human Herlitz junctional epidermolysis bullosa. Transmission electron microscopic studies showed that ablation of the Lama3 gene perturbed the formation of hemidesmosomes, which normally link the laminin-5-rich basement membrane to the keratin cytoskeleton, and disrupted the functional interaction between laminin-5 and integrin alpha-6/beta-4 (see 147557). Using tissue adhesion assays, Ryan et al. (1999) determined that in the absence of laminin-5, basal cells utilized integrin alpha-3/beta-1 (see 605025) to interact with an alternative basement membrane ligand. Using in vitro studies, Ryan et al. (1999) concluded that laminin-5-deficient epithelial cells have a survival disadvantage when compared with wildtype cells and identified conditions that allow for the rescue of mutant cells. Ryan et al. (1999) proposed that laminin-5 has an important role in regulating tissue organization, gene expression, and survival of epithelium.
Short interspersed elements (SINEs) are highly abundant components of mammalian genomes that are propagated by retrotransposition. SINEs are recognized as a causal agent of human disease, e.g., the insertion causing Fukuyama congenital muscular dystrophy (253800.0001), and must also have had a profound influence in shaping eukaryotic genomes. The B2 SINE family constitutes approximately 0.7% of total mouse genomic DNA and is also found at low abundance in humans (Mayorov et al., 2000) It resembles the Alu family in several respects, such as its mechanism of propagation. B2 SINEs are derived from tRNA and are transcribed by RNA polymerase (pol) III to generate short transcripts that are not translated. Ferrigno et al. (2001) found, however, that 1 B2 SINE also carries an active pol II promoter located outside the tRNA region. They found that a B2 element was responsible for the production of a mouse Lama3 transcript. The B2 pol II promoters can be bound and stimulated by the transcription factor USF (see USF1, 191523), as shown by transient transfection experiments. Moreover, this pol II activity does not preclude the pol III transcription necessary for retrotransposition. Dispersal of B2 SINEs by retrotransposition may therefore have provided numerous opportunities for creating regulated pol II transcription at novel genomic sites. This mechanism may have allowed the evolution of new transcription units and new genes.
Using exon-specific PCR, Graves et al. (2008) identified homozygous deletion of 6589 bp spanning exons 24 to 27 of the Lama3 gene in 10 American Saddlebred foals with junctional epidermolysis bullosa. All 10 obligate carriers were heterozygous for the deletion. The mutant Lama3 protein was predicted to lack 169 amino acids, including 111 amino acids in the LG2 domain and the first 15 amino acids of the LG3 domain. Random sampling of 175 American Saddlebreds revealed 9 that were heterozygous for the mutation, resulting in an allele frequency of 0.026 and a carrier frequency of 0.051. Assuming Hardy-Weinberg equilibrium, the expected frequency of homozygous affected foals was 0.0007.
By SNP array genotyping and autozygosity mapping in 4 Belgian Blue calves with severe epidermolysis bullosa, Sartelet et al. (2015) mapped the causative gene to an 8.3-Mb interval on bovine chromosome 24, which is orthologous to human chromosome 18. Whole-genome sequencing of an affected calf, transcriptomic data from a panel of tissues, and sequencing of positional candidates identified a G-A transition in exon 60 of the Lama3 gene that replaced arg2609 with a premature stop codon (R2609X) and truncated the Lama3 protein by 22%. Screening a cohort of 3,000 animals revealed a carrier frequency of approximately 1%.
In a patient with Herlitz junctional epidermolysis bullosa (JEB2B; 619784), Vidal et al. (1995) identified a homozygous 1-bp deletion (300delG) in the LAMA3 gene, resulting in a frameshift and premature termination. The patient's parents were first cousins. Skin biopsies showed drastically reduced immunoreactivity to antibodies directed against the alpha-3 chain of laminin-5 and impaired expression of the corresponding mRNA transcripts.
In a male infant with the lethal Herlitz form of junctional epidermolysis bullosa (JEB2B; 619784), Kivirikko et al. (1995) identified a homozygous mutation in the LAMA3 gene, resulting in an arg650-to-ter (R650X) substitution. The child was born of consanguineous Asian parents and died in early infancy.
In a Pakistani infant with Herlitz junctional epidermolysis bullosa, whose parents were consanguineous, McGrath et al. (1995) identified a homozygous 1948C-T transition in the LAMA3 gene, resulting in an R650X substitution. McGrath et al. (1996) found the same mutation in another Pakistani child with Herlitz JEB whose parents were first cousins. Studies in this family and in 2 other apparently unrelated individuals of Pakistani ancestry with the same mutation showed that all had the same haplotype, suggesting a common ancestral allele.
In a 15-month-old Saudi Arabian girl with non-Herlitz type junctional epidermolysis bullosa (JEB2A; 619783), Nakano et al. (2002) found homozygosity for a gln1368-to-ter (Q1368X) mutation in the LAMA3 gene.
In affected members of 15 consanguineous Punjabi families with laryngoonychocutaneous syndrome (JEB2C; 245660), McLean et al. (2003) identified a 1-bp insertion (151insG) in the LAMA3 gene that caused a frameshift and a predicted stop codon in an exon that is specific to the laminin alpha-3a isoform. The mutation did not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha-3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes.
In a 33-month-old Caucasian boy (patient 27) with intermediate junctional epidermolysis bullosa 2A (JEB2A; 619783), Nakano et al. (2002) detected compound heterozygosity for mutations in the LAMA3 gene: an arg1331-to-cys (R1331C) substitution, and a splice site mutation at the donor site of intron 35 (c.4651+1G-A; 600805.0006). The mutations affected globular domains III and V, respectively, of the alpha-3 chain. RT-PCR of patient keratinocytes demonstrated that the c.4651+1G-A mutation results in several alternatively spliced laminin alpha-3 polypeptides, some of which appeared to be functional. Nakano et al. (2002) concluded that the combination of c.4651+1G-A and a missense mutation (R1331C), both in the C terminus, could explain the relatively mild phenotype of the patient. The boy had blisters on his face, oral mucosa, and nail beds, with no scars or milia. Electron microscopy revealed normal hemidesmosomes, and immunofluorescence of skin biopsy showed normal laminin-5.
Intermediate Junctional Epidermolysis Bullosa 2A
For discussion of the splice donor mutation (c.4651+1G-A) in intron 35 of the LAMA3 gene that was found in compound heterozygous state in a patient with intermediate junctional epidermolysis bullosa 2A (JEB2A; 619783) by Nakano et al. (2002), see 600805.0005.
Laryngoonychocutaneous Junctional Epidermolysis Bullosa 2C
In a 7-year-old boy with laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C; 245660) Figueira et al. (2007) identified compound heterozygosity for mutations in the LAMA3 gene: a paternally inherited splice site mutation at the donor site of intron 35 (c.4651+1G-A), and a maternally inherited missense mutation, ile17-to-asn (600805.0009), that affected the laminin alpha-3a (LAMA3A) isoform.
In 2 Iranian sibs with laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C; 245660), Barzegar et al. (2013) identified homozygosity for a C-to-T substitution at nucleotide 169 (c.169C-T) in exon 39 of the LAMA3 gene (exon 1 of the laminin alpha-3a isoform), changing glutamine-57 of the laminin alpha-3a transcript to a stop codon (G57X). Two unaffected sibs as well as both parents were heterozygous carriers of this mutation. Functional studies of the mutation or of patient cells were not performed. The c.169C-T mutation occurs 18 basepairs downstream from the c.151insG mutation (600805.0004) described by McLean et al. (2003) in the Punjab families originally described with laryngoonychocutaneous syndrome (LOC).
In 2 Chinese brothers with a phenotype resembling laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C; 245660), Wang et al. (2022) identified a homozygous c.47G-A transition (c.47G-A, NM_000227.4) in exon 1 of the LAMA3A transcript (exon 39 of the LAMA3 gene) that caused a trp16-to-ter substitution (W16X). The mutation was identified using whole-exome sequencing and confirmed by Sanger sequencing. Real-time quantitative PCR showed that LAMA3A mRNA levels in the proband and brother were reduced to approximately 23% and 28%, respectively, of control values. Western blot analysis revealed that the LAMA3A protein was significantly reduced in the brothers compared to controls.
For discussion of the ile17-to-asn (I17N) mutation in the LAMA3A gene that was found in compound heterozygous state in a patient with laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C; 245660) by Figueira et al. (2007), see 600805.0006.
Barzegar, M., Mozafari, N., Kariminejad, A., Asadikani, Z., Ozoemena, L., McGrath, J. A. A new homozygous nonsense mutation in LAMA3A underlying laryngo-onycho-cutaneous syndrome. Brit. J. Derm. 169: 1353-1356, 2013. [PubMed: 23869449] [Full Text: https://doi.org/10.1111/bjd.12522]
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Ferrigno, O., Virolle, T., Djabari, Z., Ortonne, J.-P., White, R. J., Aberdam, D. Transposable B2 SINE elements can provide mobile RNA polymerase II promoters. Nature Genet. 28: 77-81, 2001. [PubMed: 11326281] [Full Text: https://doi.org/10.1038/ng0501-77]
Figueira, E. C., Crotty, A., Challinor, C. J., Coroneo, M. T., Murrell, D. F. Granulation tissue in the eyelid margin and conjunctiva in junctional epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. Clin. Exp. Ophthal. 35: 163-166, 2007. [PubMed: 17362460] [Full Text: https://doi.org/10.1111/j.1442-9071.2006.01436.x]
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Graves, K. T., Henney, P. J., Ennis, R. B. Partial deletion of the LAMA3 gene is responsible for hereditary junctional epidermolysis bullosa in the American Saddlebred Horse. Animal Genet. 40: 35-41, 2008. [PubMed: 19016681] [Full Text: https://doi.org/10.1111/j.1365-2052.2008.01795.x]
Kivirikko, S., McGrath, J. A., Baudoin, C., Aberdam, D., Ciatti, S., Dunnill, M. G. S., McMillan, J. R., Eady, R. A. J., Ortonne, J.-P., Meneguzzi, G., Uitto, J., Christiano, A. M. A homozygous nonsense mutation in the alpha-3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. Hum. Molec. Genet. 4: 959-962, 1995. [PubMed: 7633458] [Full Text: https://doi.org/10.1093/hmg/4.5.959]
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McGrath, J. A., Kivirikko, S., Ciatti, S., Moss, C., Christiano, A. M., Uitto, J. A recurrent homozygous nonsense mutation within the LAMA3 gene as a cause of Herlitz junctional epidermolysis bullosa in patients of Pakistani ancestry: evidence for a founder effect. J. Invest. Derm. 106: 781-784, 1996. [PubMed: 8618022] [Full Text: https://doi.org/10.1111/1523-1747.ep12346349]
McGrath, J. A., Kivirikko, S., Ciatti, S., Moss, C., Dunnill, M. G. S., Eady, R. A. J., Rodeck, C. H., Christiano, A. M., Uitto, J. A homozygous nonsense mutation in the alpha-3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. Genomics 29: 282-284, 1995. [PubMed: 8530087] [Full Text: https://doi.org/10.1006/geno.1995.1246]
McLean, W. H. I., Irvine, A. D., Hamill, K. J., Whittock, N. V., Coleman-Campbell, C. M., Mellerio, J. E., Ashton, G. S., Dopping-Hepenstal, P. J. H., Eady, R. A. J., Jamil, T., Phillips, R. J., Shabbir, S. G., Haroon, T. S., Khurshid, K., Moore, J. E., Page, B., Darling, J., Atherton, D. J., van Steensel, M. A. M., Munro, C. S., Smith, F. J. D., McGrath, J. A. An unusual N-terminal deletion of the laminin alpha-3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum. Molec. Genet. 12: 2395-2409, 2003. Note: Erratum: Hum. Molec. Genet. 13: 365 only, 2004. [PubMed: 12915477] [Full Text: https://doi.org/10.1093/hmg/ddg234]
Nakano, A., Chao, S.-C., Pulkkinen, L., Murrell, D., Bruckner-Tuderman, L., Pfendner, E., Uitto, J. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs non-Herlitz phenotypes. Hum. Genet. 110: 41-51, 2002. [PubMed: 11810295] [Full Text: https://doi.org/10.1007/s00439-001-0630-1]
Ryan, M. C., Lee, K., Miyashita, Y., Carter, W. G. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells. J. Cell Biol. 145: 1309-1323, 1999. [PubMed: 10366601] [Full Text: https://doi.org/10.1083/jcb.145.6.1309]
Ryan, M. C., Tizard, R., VanDevanter, D. R., Carter, W. G. Cloning of the LamA3 gene encoding the alpha-3 chain of the adhesive ligand epiligrin: expression in wound repair. J. Biol. Chem. 269: 22779-22787, 1994. [PubMed: 8077230]
Sartelet, A., Harland, C., Tamma, N., Karim, L., Bayrou, C., Li, W., Ahariz, N., Coppieters, W., Georges, M., Charlier, C. A stop-gain in the laminin, alpha 3 gene causes recessive junctional epidermolysis bullosa in Belgian Blue cattle. Animal Genet. 46: 566-570, 2015. [PubMed: 26370913] [Full Text: https://doi.org/10.1111/age.12342]
Taniuchi, K., Takata, M., Matsui, C., Fushida, Y., Uchiyama, K., Mori, T., Kawara, S., Yancey, K. B., Takehara, K. Antiepiligrin (laminin 5) cicatricial pemphigoid associated with an underlying gastric carcinoma producing laminin 5. Brit. J. Derm. 140: 696-700, 1999. [PubMed: 10233324] [Full Text: https://doi.org/10.1046/j.1365-2133.1999.02773.x]
Vidal, F., Baudoin, C., Miquel, C., Galliano, M.-F., Christiano, A. M., Uitto, J., Ortonne, J.-P., Meneguzzi, G. Cloning of the laminin alpha-3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics 30: 273-280, 1995. [PubMed: 8586427] [Full Text: https://doi.org/10.1006/geno.1995.9877]
Wang, R., Sun, L., Habulieti, X., Liu, J., Guo, K., Yang, X., Ma, D., Zhang, X. Novel variants in LAMA3 and COL7A1 and recurrent variant in KRT5 underlying epidermolysis bullosa in five Chinese families. Front. Med. 16: 808-814, 2022. [PubMed: 35314946] [Full Text: https://doi.org/10.1007/s11684-021-0878-x]