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It is generally acknowledged that Laminins are heterotrimeric complexes that consist of α, β and γ subunits, forming a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping functions and distributions.
Through the combination of homozygosity mapping and whole-exome sequencing(Fig. 1), researchers were able to determine biallelic mutations in LAMA1 as the cause of Cerebellar dysplasia with cysts (CDC) in seven affected individuals, independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Among these individuals, most of them have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. After idetifying two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts in one additional family, it can be indicated that cysts are not an obligate feature associated with loss of LAMA1 function.
Fig. 1. LD patterns of the LAMA1 locus. Pairwise LD between SNPs within LAMA1 locus are evaluated by D′ Structures of low to high LD in the LAMA1 locus are shown in colored region. The case is above and the control is below the diagonal line. (M Ota et al, 2007)
Researchers also investigated the role of LAMA1 in the development of proliferative diabetic retinopathy (PDR). Retinal choroidal vascular endothelial cells (RF/6A line) were exposed to glucose at different concentrations and analyzed for cell growth, migration, proliferation, and adhesion. LAMA1 expression was also examined following glucose treatment. The results indicated that the proliferation, migration, and adhesion of RF/6A cells were increased by high glucose, while LAMA1 expression was slightly higher at 1565mM but decreased at 2565mM and 3565mM glucose compared to control. Thus, it would be reasonable to connect changes in the biological behavior of high glucose-exposed retinal vascular endothelial cells with variations in LAMA1 expression. This suggests a possibility for LAMA1 involvement in PDR development.
To investigate the role of LAMA1 in pathological myopia (PM) at the transcriptional level, researchers investigated the binding affinity of single nucleotide polymorphism (SNP) rs2089760-located on the LAMA1 promoter gene-to human fetal scleral fibroblast (HFSF) nucleoprotein and analyzed its effect on LAMA1 transcriptional initiation activity. Results revealed that both specific and mutant probes banded precisely with HFSF nucleoprotein. These findings suggest the possibility that SNP rs2089760 from the LAMA1 promoter region located at the transcription factor binding site. The SNP rs2089760 G > A mutation negatively regulates gene transcription of LAMA1, and reduces transcription factor binding ability and transcriptional initiation activity.
Investigators also reported siblings with Poretti-Boltshauser syndrome (PBS), who displayed a retinal phenotype similar to familial exudative vitreoretinopathy (FEVR) with widespread retinal avascularity. Also, among them, 1 sibling exhibited retinal neovascularization. These cases together suggest a role for LAMA1 in retinal vascular disease and also as a potential novel locus for FEVR.
Researchers have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with LAMA1-associated lamininopathy under clinical protocol, NCT00068224. With the use of patient-derived fibroblasts and neuronal cells derived from neuronal stem cells, researchers were able to investigate the consequence of mutations in LAMA1. It appears that in individuals with biallelic mutations in LAMA1, all had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. LAMA1 knockdown in human neuronal cells exhibited abnormal morphology and filopodia formation. This serves as evidence for the importance of LAMA1 in neuronal migration. The phenotypes associated with LAMA1 mutations were broadened. It was also demonstrated that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics.