Disease relevance of LAMA2

• Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci [1].
• In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-beta1 [2].

High impact information on LAMA2

• Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy [3].
• The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein [3].
• LAMA2 deposition around muscle fibers was often segmental and seemed to radiate from the center to the periphery of the injection site [4].
• However, not all myoblasts, or myoblasts alone, or the muscle fibers they form are capable of LAMA2 secretion and deposition in vivo [4].
• Following the discovery of merosin deficiency in some CMD cases, we have localized, by homozygosity mapping and linkage analysis (Zmax = 5.6; theta = 0.0 for marker AFM127xb2) in four merosin-negative families a CMD gene in a 16 cM region of chromosome 6q2 in the region of the laminin M chain gene [5].

Biological context of LAMA2

• Two forms are defined at the molecular level: merosin deficient-CMD caused by mutations in the LAMA2-gene on chromosome 6q2 [6].
• Comparison of the exon pattern of the human LAMA2 gene with that of the Drosophila LAMA gene revealed that only 2 of 63 intron locations in the 5'-end of the human gene match the intron locations in the Drosophila gene, which contains 14 introns [7].
• These mutations cause a disruption of the open reading frame of LAMA2 [8].
• In 2 patients, the Cys967Stop mutation and identical haplotypes flanking the LAMA2 gene indicated a founder effect [9].
• CONCLUSIONS: The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression [9].

Anatomical context of LAMA2

• The laminina2-chain gene (LAMA2) encodes a basal lamina protein, laminina2, known to be deficient in one form of congenital muscular dystrophy (CMD) [8].
•  [10].
• We studied both laminin-alpha 2 chain expression in trophoblast using immunocytochemistry and linkage analysis to the LAMA2 locus [11].
• This case provides new evidence of the phenotypical heterogeneity of the LAMA2 gene and sheds light in understanding the role of laminin alpha 2 chain in myelination of peripheral nerve [12].
• The CMD1A form is caused by a deficiency of the alpha2 chain of laminin 2 (LAMA2 gene at 6q2), a protein present in the basal lamina of muscle fibers, in Schwann cells, epidermis, and in fetal trophoblastic tissue [13].

Associations of LAMA2 with chemical compounds

• Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases [14].
• All subjects were undergoing opiate detoxification with either methadone or the longer-acting 1-alpha acetylmethadol (LAMM) [15].

Other interactions of LAMA2

• Although closely linked to LAMA2, the LAMA4 product most closely resembles laminin alpha 3, a constituent of laminin 5 [16].
• LAMA2 mutations were undetected in 5 patients, in 2 of whom FKRP mutations explained the phenotype [9].
• Haplotype analysis using microsatellite markers excluded the Fukuyama congenital muscular dystrophy, LAMA2 and muscle-eye-brain disease loci [17].
• In a laminina2 deficient-CMD patient, we screened the entire LAMA2 cDNA (953bp) by reverse transcriptase polymerase chain reaction combined with single strand conformational polymorphism analysis [8].
• The LAMA2 mutations induce the formation of abnormal laminins which probably dramatically disturb the assembly and stability of the laminin network, one of the major components of the extracellular matrix in skeletal muscle [18].

Analytical, diagnostic and therapeutic context of LAMA2

• LAMA2 gene analysis in congenital muscular dystrophy: new mutations, prenatal diagnosis, and founder effect [9].
• Typical white matter alterations on magnetic resonance imaging were found in all patients with LAMA2 mutations, supporting the utility of magnetic resonance imaging in differential diagnosis [9].
• Motor and sensory nerve conduction velocities (NCVs) and needle electromyography (EMG) results were reviewed in 26 children with different types of congenital muscular dystrophy (CMD), including patients with mutations in the genes LAMA2, FKRP, and COL6A2 [19].
• All transplanted animals expressed LAMA2 in these immunologically-controlled models, and the degrees of LAMA2 restoration were shown to depend on the age of the animal at transplantation, on muscle pretreatment, and on duration time after transplantation in some cases [4].
• Mutations in LAMA2 cause CMD with complete or partial merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for approximately 50% of CMD cases [20].

References