Alternative titles; symbols
HGNC Approved Gene Symbol: LAMC2
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38): 1:183,186,264-183,258,968 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Epidermolysis bullosa, junctional 3A, intermediate | 619785 | Autosomal recessive | 3 |
| Epidermolysis bullosa, junctional 3B, severe | 619786 | 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 (LAMA3; 600805), beta-3 (LAMB3; 150310), and gamma-2 (LAMC2) 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).
Kallunki et al. (1992) isolated 2 novel cDNAs from a human fibrosarcoma cell library, one encoding a deduced 1,193-amino acid protein and the other encoding a deduced 1,111-amino acid protein. One of these proteins, which Kallunki et al. (1992) designated LAMB2T (LAMC2), was homologous to what was then termed laminin B2 (now termed LAMC1, 150290) but was significantly shorter. Northern blot analysis of human fetal tissues showed highest expression of LAMC2 in skin and lung, and lower expression in kidney, thymus, choroid plexus, cerebellum, and the brain intermediate zone. In situ hybridization localized LAMC2 to specific epithelial cells in skin, lung, and kidney as opposed to a general epithelial and endothelial cell expression of LAMC1 in the same tissues.
By in situ hybridization, Kallunki et al. (1992) demonstrated that the LAMC2 gene maps to chromosome 1q25-q31 in close proximity to the LAMC1 gene.
Aberdam et al. (1994) mapped the homologous gene in the mouse to chromosome 1 by isotopic in situ hybridization. They concluded that the mouse genes encoding the 100-kD and the 125-kD subunits of nicein are both on mouse chromosome 1 in band H1 and in the region of bands H2-6, respectively, whereas the gene encoding the 150-kD subunit of mouse nicein is located in the A band of chromosome 18.
Stumpf (2022) mapped the LAMC2 gene to chromosome 1q25.3 based on an alignment of the LAMC2 sequence (GenBank BC113378) with the genomic sequence (GRCh38).
Airenne et al. (1996) determined the structure of the LAMC2 gene, which contains 23 exons and spans approximately 55 kb. The 2 cDNAs described by Kallunki et al. (1992) were shown to result from alternative splicing. The long form includes exon 23, whereas the short form encodes a protein that truncates 2 codons beyond exon 22.
Airenne et al. (1996) found that in 17-week old human embryonic tissues the long form of LAMC2 was strongly expressed in the epithelia of all tissues, whereas mRNA for the short form was observed in the cerebral cortex, lung, and distal tubules of the kidney.
Intermediate Junctional Epidermolysis Bullosa 3A
Nakano et al. (2002) identified a mutation in the LAMC2 gene (R245X; 150292.0006) in a patient with non-Herlitz JEB (JEB3A; 619785). Nakano et al. (2002) examined the molecular basis of the specification of Herlitz versus non-Herlitz forms of JEB. They examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz JEB, for mutations in the candidate genes LAMA3, LAMB3, and LAMC2. The mutation detection strategy consisted of PCR amplification of all exons in these genes, followed by heteroduplex scanning and sequencing. They were able to identify pathogenic mutations in both alleles of each proband, the largest number of mutations being in the LAMB3 gene. Examination of the mutation database, which provided clinical information, revealed that most cases with Herlitz JEB harbored premature termination codon (PTC) mutations in both alleles. In non-Herlitz cases, the PTC mutation was frequently associated with a missense mutation or a putative splicing mutation in trans. In 3 cases with putative splicing mutations, RT-PCR analysis revealed a repertoire of splice variants in-frame, predicting the synthesis of either shortened or lengthened, yet partly functional, polypeptides. These observations would explain the relatively mild phenotype in cases with splicing mutations.
Severe Junctional Epidermolysis Bullosa 3B
In a patient with the Herlitz form of junctional epidermolysis bullosa (JEB3B; 619786), Pulkkinen et al. (1994) identified a homozygous mutation in the LAMC2 gene (150292.0001).
Aberdam et al. (1994) found mutations in the LAMC2 gene in patients with Herlitz JEB. Linkage studies indicated close linkage to microsatellite markers in the region of chromosome 1 where the LAMC2 gene had previously been mapped. The approach of homozygosity mapping was used in part.
In a girl with the Herlitz-Pearson type of junctional epidermolysis bullosa (JEB3B; 619786), Pulkkinen et al. (1994) identified a homozygous G-to-A transition in intron 8 of the LAMC2 gene, resulting in the skipping of exon 9. The deletion was predicted to result in shortening of the kalinin gamma-2 chain by 73 amino acids within subdomains III and IV. The patient had multiple erosions and hemorrhagic blisters. She had lost nails from the fingers and toes, but there was no fusion of digits. She died at age 23. A similarly affected older sister had died at age 21. The parents were reportedly unaffected. Since the first nucleotide of exon 9 is 1184, Pulkkinen et al. (1994) referred to this mutation as 1184,-1,G-to-A.
In affected members of a family with Herlitz junctional epidermolysis bullosa (JEB3B; 619786), Aberdam et al. (1994) identified a homozygous C-to-T transition in exon 3 of the LAMC2 gene, resulting in an arg95-to-ter (R95X) substitution. Clinical features included extensive blistering and erosion of the skin shortly after birth. Blisters were located within the lamina lucida of the dermoepidermal basement membrane, with an intact epidermis at the roof and an intact lamina densa at the base.
In affected members of a family with the Herlitz type of junctional epidermolysis bullosa (JEB3B; 619786), Baudoin et al. (1994) observed a homozygous 1182C-G transversion in the LAMC2 gene, resulting in a tyr355-to-ter (Y355X) substitution.
In a patient of Japanese origin with Herlitz junctional epidermolysis bullosa (JEB3B; 619786), Takizawa et al. (2000) identified a homozygous C-to-A substitution at position 1776 of exon 11 of the LAMC2 gene. This resulted in a cys553-to-ter (C553X) nonsense mutation. The patient died at 8 months of age. The father was a heterozygous carrier of this mutation, whereas the mother had 2 normal LAMC2 alleles. The patient showed homozygosity for 15 known intragenic polymorphisms in the LAMC2 gene and 16 microsatellite markers spanning the entire chromosome 1 which, when informative, were paternal in origin.
In a Caucasian male with Herlitz junctional epidermolysis bullosa (JEB3B; 619786) who died at the age of 4 months with generalized blistering and abnormal nails, Nakano et al. (2002) found homozygosity for a 7-bp deletion (2137del7) in the LAMC2 gene.
In a 7-year-old Turkish girl with junctional epidermolysis bullosa of the non-Herlitz type (JEB3A; 619785) manifested as generalized moderate blisters with nail and dental abnormalities, Nakano et al. (2002) found homozygosity for an arg245-to-ter (R245X) nonsense mutation in exon 6 of the LAMC2 gene.
In a compound heterozygous non-Herlitz junctional epidermolysis bullosa (JEB3A; 619785) patient, Castiglia et al. (2001) described a de novo LAMC2 splice site mutation, 522-1G-A. This mutation resulted in in-frame skipping of exon 4 and synthesis of a mutated gamma-2 polypeptide (gamma-2-delta-4) carrying a 33-amino acid deletion within the N-terminal domain V. Transfection of this mutant cDNA into LAMC2-null keratinocytes resulted in restoration of laminin-5 deposition onto the culture substrate, which demonstrated that the gamma-2 polypeptides carrying a deletion in domain V, upstream of the gamma-2 proteolytic cleavage site, are assembled into native laminin-5 that is secreted and extracellularly processed. The mutation carried on the other allele of the patient (150292.0008) did not result in laminin-5 secretion and extracellular processing.
In a compound heterozygous non-Herlitz junctional epidermolysis bullosa (JEB3A; 619785) patient, Castiglia et al. (2001) described a 1-basepair insertion (3511insA) in the 3-prime terminal exon of LAMC2, resulting in a frameshift and a premature termination codon. This mutation was predicted to lead to the synthesis of a gamma-2 polypeptide (gamma-2t) disrupted in its alpha-helical C-terminal structure and truncated of the last 25 amino acids. Transfection of this mutant cDNA into LAMC2-null keratinocytes failed to restore laminin-5 immunoreactivity, which indicated that integrity of the gamma-2 C-terminal amino acid sequences is required for laminin-5 assembly. The other allele of the patient carried a splice site mutation (150292.0007).
Aberdam, D., Galliano, M. F., Mattei, M.-G., Pisani-Spadafora, A., Ortonne, J. P., Meneguzzi, G. Assignment of mouse nicein genes to chromosomes 1 and 18. Mammalian Genome 5: 229-233, 1994. [PubMed: 8012114] [Full Text: https://doi.org/10.1007/BF00360551]
Aberdam, D., Galliano, M.-F., Vailly, J., Pulkkinen, L., Bonifas, J., Christiano, A. M., Tryggvason, K., Uitto, J., Epstein, E. H., Jr., Ortonne, J.-P., Meneguzzi, G. Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma-2 subunit of nicein/kalinin (laminin-5). Nature Genet. 6: 299-304, 1994. [PubMed: 8012394] [Full Text: https://doi.org/10.1038/ng0394-299]
Airenne, T., Haakana, H., Sainio, K., Kallunki, T., Kallunki, P., Sariola, H., Tryggvason, K. Structure of the human laminin gamma-2 chain gene (LAMC2): alternative splicing with different tissue distribution of two transcripts. Genomics 32: 54-64, 1996. [PubMed: 8786121] [Full Text: https://doi.org/10.1006/geno.1996.0076]
Baudoin, C., Miquel, C., Gagnoux-Palacios, L., Pulkkinen, L., Christiano, A. M., Uitto, J., Tadini, G., Ortonne, J.-P., Meneguzzi, G. A novel homozygous nonsense mutation in the LAMC2 gene in patients with the Herlitz junctional epidermolysis bullosa. Hum. Molec. Genet. 3: 1909-1910, 1994. [PubMed: 7849725] [Full Text: https://doi.org/10.1093/hmg/3.10.1909]
Burgeson, R. E., Chiquet, M., Deutzmann, R., Ekblom, P., Engel, J., Kleinman, H., Martin, G. R., Meneguzzi, G., Paulsson, M., Sanes, J., Timpl, R., Tryggvason, K., Yamada, Y., Yurchenco, P. D. A new nomenclature for the laminins. Matrix Biol. 14: 209-211, 1994. [PubMed: 7921537] [Full Text: https://doi.org/10.1016/0945-053x(94)90184-8]
Castiglia, D., Posteraro, P., Spirito, F., Pinola, M., Angelo, C., Puddu, P., Meneguzzi, G., Zambruno, G. Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. J. Invest. Derm. 117: 731-739, 2001. [PubMed: 11564184] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01453.x]
Kallunki, P., Sainio, K., Eddy, R., Byers, M., Kallunki, T., Sariola, H., Beck, K., Hirvonen, H., Shows, T. B., Tryggvason, K. A truncated laminin chain homologous to the B2 chain: structure, spatial expression, and chromosomal assignment. J. Cell Biol. 119: 679-693, 1992. [PubMed: 1383240] [Full Text: https://doi.org/10.1083/jcb.119.3.679]
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]
Pulkkinen, L., Christiano, A. M., Airenne, T., Haakana, H., Tryggvason, K., Uitto, J. Mutations in the gamma-2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. Nature Genet. 6: 293-298, 1994. [PubMed: 8012393] [Full Text: https://doi.org/10.1038/ng0394-293]
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]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/29/2022.
Takizawa, Y., Pulkkinen, L., Chao, S.-C., Nakajima, H., Nakano, Y., Shimizu, H., Uitto, J. Mutation report: complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa. J. Invest. Derm. 115: 307-311, 2000. [PubMed: 10951251] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00052.x]