HGNC Approved Gene Symbol: LAMB1
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38) : 7:107,923,799-108,003,161 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.1 | Lissencephaly 5 | 615191 | Autosomal recessive | 3 |
The major components of basal laminae are the glycoproteins laminin and collagen IV (see 120130), both of which are heterotrimers. Laminin is a cruciform protein trimer of chains that when originally isolated from the extracellular matrix of tumor cells, were named A, B1, and B2, but were renamed alpha-1, beta-1, and gamma-1, respectively (Burgeson et al., 1994). The laminin and collagen IV isoforms vary from one basal lamina to another and are members of multigene families. These gene families (like others, such as the globins and myosins) may provide a means of generating functional diversity within a common structural framework.
Laminin functions in relation to epithelial cells and type IV collagen in the manner that fibronectin (135600) does for type I collagen and tissue cells of many types and that chondronectin (118670) does for type II collagen and chondrocytes. It is present in serum in very low concentration (about 1 microg/ml) and indeed the laminin measured in serum by immunoassay may be in fragments. It binds heparin and heparin sulfate also (Kleinman, 1982). The laminin molecule, of approximately 1 million daltons, is composed of one A chain (about 400,000 daltons) and three beta chains (about 200,000 daltons), held together by interchain disulfide bonds. Three species of B chains have been described. It is likely that the laminins may vary with regard to B chain composition. The B1 and B2 laminin genes, which are coordinately regulated with alpha-1(IV) (120130) and alpha-2(IV) (120090) collagen genes, are tightly linked on mouse chromosome 1 (Elliott et al., 1985).
Sasaki et al. (1987) reported the sequence of cDNA encoding the laminin B1 chain. Modi et al. (1987) isolated a partial cDNA clone of the human gene encoding the laminin B1 chain. After identifying a sequence in the B1 chain that is involved in cell attachment, chemotaxis, and binding to the laminin receptor, Iwamoto et al. (1987) tested this nonapeptide and its amide form as well as other peptides for their capacity to inhibit the formation of metastases. Specifically, a pentapeptide from the nonapeptide sequence was found to reduce the formation of lung colonies in mice injected with melanoma cells and also to inhibit the invasiveness of the cells in vitro.
In mice, Radmanesh et al. (2013) found ubiquitous and strong expression of the Lamb1 gene in the whole E10 embryo, in the E14, E16, P0, and F15 forebrain, and in P15 cerebellum and muscle. Expression in embryonic meninges was also strong. Immunostaining of mouse brain at postnatal day 7 showed high levels of Lamb1 in the cerebellar basement membrane. Expression in the eye globe was lower compared to that in other tissues.
From genomic clones, Vuolteenaho et al. (1990) determined that the LAMB1 gene spans 80 kb. DNA sequencing and heteroduplex analyses demonstrated that the gene has 34 exons. The intron sizes varied from 92 to more than 15,000 basepairs. In fact, since their clones did not contain all of introns 13 and 14, the exact size of the gene remained undetermined.
Using Xenopus, Hopker et al. (1999) demonstrated that laminin-1-beta from the extracellular matrix converts netrin (601614)-mediated attraction into repulsion. A soluble peptide fragment of laminin-1-beta (YIGSR) mimicked this laminin-induced conversion. Low levels of cAMP in growth cones also led to the conversion of netrin-induced attraction into repulsion, and Hopker et al. (1999) showed that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich optic nerve head, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. Hopker et al. (1999) concluded that extracellular matrix molecules not only promote axon outgrowth, but also modify the behavior of growth cones in response to diffusible guidance cues.
In a human brain transcriptome, Radmanesh et al. (2013) found that LAMB1 expression was correlated with expression of other genes involved in cortical lamination, including ZIC1 (600470), ZIC2 (603073), and genes encoding collagens, such as COL3A1 (120180), and other laminins, such as LAMC3 (604349), suggesting a genetic network regulating pial basement membrane function in the brain.
Modi et al. (1987) mapped the LAMB1 locus to 7q31.1-q31.3 by Southern blot analysis of somatic cell hybrids and by in situ hybridization. On the other hand, by the same methods, Pikkarainen et al. (1987) placed LAMB1 in the 7q22 band. Jaye et al. (1987) regionalized LAMB1 to band 7q31 by somatic cell hybridization and in situ hybridization.
In 4 patients from 2 unrelated consanguineous families with lissencephaly-5 (LIS5; 615191), Radmanesh et al. (2013) identified 2 different homozygous loss-of-function mutations in the LAMB1 gene (150240.0001 and 150240.0002, respectively). Both mutations were identified by exome sequencing. The brain malformations were characterized by cobblestone changes in the cortex, more severe in the posterior region, and subcortical band heterotopia. Clinically, the patients had hydrocephalus, seizures, and severely delayed psychomotor development. The findings suggested a role for LAMB1 at the basement membrane, where it mediates both the integrity of the glia limitans and attachment of radial glial endfeet during neuronal migration.
In 2 adult sibs, born of unrelated parents, with LIS5, Tonduti et al. (2015) identified compound heterozygous mutations in the LAMB1 gene: a frameshift mutation (150240.0003) and a missense substitution (C481F; 150240.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
Burgeson et al. (1994), a group of 14 leading researchers in the field of connective tissue proteins, adopted a new nomenclature for the laminins. They were numbered with arabic numerals in the order discovered. The previous A, B1, and B2 chains, and their isoforms, are alpha, beta, and gamma, respectively, followed by an arabic numeral to identify the isoform. For example, the first laminin identified from the Engelbreth-Holm-Swarm tumor (EHS) was designated laminin-1 with the chain composition alpha-1/beta-1/gamma-1. The genes for these 3 chains are LAMA1 (150320), LAMB1, and LAMC1 (150290).
In 3 sibs, born of consanguineous Egyptian parents, with lissencephaly-5 (LIS5; 615191), Radmanesh et al. (2013) identified a homozygous 14-bp deletion/41-bp insertion (c.3145_3158delins41) in exon 22 of the LAMB1 gene, resulting in a frameshift and premature termination (Lys1049Profs*7) in a laminin EGF-like domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in several large control databases, 100 Egyptian individuals, or more than 2,000 in-house exomes. Linkage analysis of the family was consistent with the location of the causative mutation to chromosome 7q22.
In a Turkish patient, born of consanguineous parents, with lissencephaly-5 (LIS5; 615191), Radmanesh et al. (2013) identified a homozygous G-to-T transversion in intron 16 of the LAMB1 gene (c.2110+1G-T), resulting in abnormal splicing and a frameshift (Ser703fsTer62). The mutation, which was found by exome sequencing, was not present in several large control databases, 100 Turkish individuals, or more than 2,000 in-house exomes.
In 2 adult sibs, born of unrelated parents, with lissencephaly-5 (LIS5; 615191), Tonduti et al. (2015) identified compound heterozygous mutations in the LAMB1 gene: a 1-bp deletion (c.2931del), resulting in a frameshift and premature termination (Gln977HisfsTer84), and a c.1442G-T transversion, resulting in a cys481-to-phe (C481F; 150240.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in 100 control chromosomes. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1442G-T transversion, resulting in a cys481-to-phe (C481F) substitution, in the LAMB1 gene that was found in compound heterozygous state in 2 sibs with lissencephaly-5 (LIS5; 615191) by Tonduti et al. (2015), see 150240.0003.
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]
Elliott, R. W., Barlow, D., Hogan, B. L. M. Linkage of genes for laminin B1 and B2 subunits on chromosome 1 in mouse. In Vitro Cell Dev. Biol. 21: 477-484, 1985. [PubMed: 2993224] [Full Text: https://doi.org/10.1007/BF02620837]
Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 401: 69-73, 1999. [PubMed: 10485706] [Full Text: https://doi.org/10.1038/43441]
Iwamoto, Y., Robey, F. A., Graf, J., Sasaki, M., Kleinman, H. K., Yamada, Y., Martin, G. R. YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation. Science 238: 1132-1134, 1987. Note: Erratum: Science 239: 245 only, 1988. [PubMed: 2961059] [Full Text: https://doi.org/10.1126/science.2961059]
Jaye, M., Modi, W. S., Ricca, G. A., Mudd, R., Chiu, I.-M., O'Brien, S. J., Drohan, W. N. Isolation of a cDNA clone for the human laminin-B1 chain and its gene localization. Am. J. Hum. Genet. 41: 605-615, 1987. [PubMed: 3661559]
Kleinman, H. K. Personal Communication. Bethesda, Md. 1/7/1982.
Modi, W. S., Jaye, M., O'Brien, S. J. Chromosomal localization of a cDNA clone for the human B1 laminin chain. (Abstract) Cytogenet. Cell Genet. 46: 663 only, 1987.
Pikkarainen, T., Eddy, R., Fukushima, Y., Byers, M., Shows, T., Pihlajaniemi, T., Saraste, M., Tryggvason, K. Human laminin B1 chain: a multidomain protein with gene (LAMB1) locus in the q22 region of chromosome 7. J. Biol. Chem. 262: 10454-10462, 1987. [PubMed: 3611077]
Pikkarainen, T., Savolainen, E.-R., Tryggvason, K. Nhe I and Hinc II polymorphisms in the human laminin B1 chain gene on 7q22. Nucleic Acids Res. 17: 4424 only, 1989. [PubMed: 2567987] [Full Text: https://doi.org/10.1093/nar/17.11.4424]
Radmanesh, F., Caglayan, A. O., Silhavy, J. L., Yilmaz, C.., Cantagrel, V., Omar, T., Rosti, B., Kaymakcalan, H., Gabriel, S., Li, M., Sestan, N., Bilguvar, K., Dobyns, W. B., Zaki, M. S., Gunel, M., Gleeson, J. G. Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities. Am. J. Hum. Genet. 92: 468-474, 2013. [PubMed: 23472759] [Full Text: https://doi.org/10.1016/j.ajhg.2013.02.005]
Sasaki, M., Kato, S., Kohno, K., Martin, G. R., Yamada, Y. Sequence of the cDNA encoding the laminin B1 chain reveals a multidomain protein containing cysteine-rich repeats. Proc. Nat. Acad. Sci. 84: 935-939, 1987. [PubMed: 3493487] [Full Text: https://doi.org/10.1073/pnas.84.4.935]
Tonduti, D., Dorboz, I., Renaldo, F., Masliah-Planchon, J., Elmaleh-Berges, M., Dalens, H., Rodriguez, D., Boespflug-Tanguy, O. Cystic leukoencephalopathy with cortical dysplasia related to LAMB1 mutations. Neurology 84: 2195-2197, 2015. [PubMed: 25925986] [Full Text: https://doi.org/10.1212/WNL.0000000000001607]
Vuolteenaho, R., Chow, L. T., Tryggvason, K. Structure of the human laminin B1 chain gene. J. Biol. Chem. 265: 15611-15616, 1990. [PubMed: 1975589]