Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome

Abstract

Background: We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin β2 subunit ( LAMB2 ). Methods and results: Mutational analysis in the affected patient, who has a history of a serious untoward reaction to treatment with acetylcholinesterase inhibition, revealed two frame-shifting heteroallelic mutations, a maternally inherited 1478delG and a paternally inherited 4804delC . An anconeus muscle biopsy demonstrated a profound distortion of the architecture and function of the neuromuscular junction, which was strikingly similar to that seen in mice lacking laminin β2 subunit. The findings included: pronounced reduction of the axon terminal size with encasement of the nerve endings by Schwann cells, severe widening of the primary synaptic cleft and invasion of the synaptic space by the processes of Schwann cells, and moderate simplification of postsynaptic folds and intact expression of the endplate acetylcholinesterase. The endplate potential quantal content was notably reduced, while the frequencies and amplitudes of miniature endplate potentials were only moderately diminished and the decay phases of miniature endplate potentials were normal. Western blot analysis of muscle and kidney tissue and immunohistochemistry of kidney tissue showed no laminin β2 expression. Conclusion: This case, which represents a new type of synaptic CMS, exemplifies the wide variability of phenotypes associated with LAMB2 mutations and underscores the fundamental role that laminin β2 plays in the development of the human neuromuscular junction.

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…The kinetic mutations fall into two categories according to whether they induce slow or fast channel syndromes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

“…[4][5] To date 13 genes have been found to cause CMS when mutated. These are the pre-synaptic acetyltransferase CHAT 6 , the gene COLQ 7-8-9 encoding the triple stranded collagenic tail of the synaptic acetylcholinesterase (AChE), the genes encoding the different subunits of the postsynaptic acetylcholine receptors (AChR) CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG, the RAPSN gene encoding the postsynaptic protein rapsyn 10 , the postsynaptic muscle specific kinase (MUSK) gene 11 , the postsynaptic sodium channel (SCN4) 12 , the DOK7 gene encoding the postsynaptic Dok-7 protein [13][14] , the LAMB2 encoding the synaptic Laminin B2 protein 15 , the AGRN gene encoding the postsynaptic agrin protein 16 and the PLEC1 gene encoding the postsynaptic protein plectin. 17-18-19 Genetic classification of the different CMS cohorts reveals that the majority of CMS patients have mutations in genes expressing postsynaptic endplate proteins [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (table 1).…”

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials Sine et al, 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate Milone et al, 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al, 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al, 2004;Chevessier et al, 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity Hamuro et al, 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al, 1999;Selcen et al, 2011), (vii) glutamine-fructose-6-phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al, 2011), (viii) skeletal muscle sodium channel type 1.4 (Na V 1.4) that spreads depolarization potential from endplate throughout muscle fibers , (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina Kimbell et al, 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al, 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al, 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al, 2001;Cole et al, 2008), and LRP4 (Higuchi et al, 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.…”

Basement membranes and human disease

“…These defects include invasion of Schwann cell in the synaptic space and structural defects leading to muscle weakness and fatigability (Maselli et al 2009), symptoms also observed in Lamb2 -/-mice (Patton et al 1998). The mice also exhibit congenital nephrosis (Noakes et al 1995b), retinal defects (Libby et al 1999) and failure to thrive.…”

“…Due to better management of renal problems, Pierson syndrome patients' life expectancy has increased and led to the manifestation of a neuromuscular phenotype in some individuals (Maselli et al 2009;Wuhl et al 2007). These defects include invasion of Schwann cell in the synaptic space and structural defects leading to muscle weakness and fatigability (Maselli et al 2009), symptoms also observed in Lamb2 -/-mice (Patton et al 1998).…”