title: Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE.
abstract: Mutations in the plectin gene (PLEC1) cause epidermolysis bullosa simplex (EBS), which may associate with muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). The association of EBS with congenital myasthenic syndrome (CMS) is also suspected to result from PLEC1 mutations. We report here a consanguineous patient with EBS and CMS for whom mutational analysis of PLEC1 revealed a homozygous 36 nucleotide insertion (1506_1507ins36) that results in a reduced expression of PLEC1 mRNA and plectin in the patient muscle. In addition, mutational analysis of CHRNE revealed a homozygous 1293insG, which is a well-known low-expressor receptor mutation. A skin biopsy revealed signs of EBS, and an anconeus muscle biopsy showed signs of a mild myopathy. Endplate studies showed fragmentation of endplates, postsynaptic simplification, and large collections of thread-like mitochondria. Amplitudes of miniature endplate potentials were diminished, but the endplate quantal content was actually increased. The complex phenotype presented here results from mutations in two separate genes. While the skin manifestations are because of the PLEC1 mutation, footprints of mutations in PLEC1 and CHRNE are present at the neuromuscular junction of the patient indicating that abnormalities in both genes contribute to the CMS phenotype.
authors.affiliation: Department of Neurology, University of California Davis, USA. ramaselli@ucdavis.edu
authors.forename: R A
authors.initials: RA
authors.lastname: Maselli
authors.forename: J
authors.initials: J
authors.lastname: Arredondo
authors.forename: O
authors.initials: O
authors.lastname: Cagney
authors.forename: T
authors.initials: T
authors.lastname: Mozaffar
authors.forename: S
authors.initials: S
authors.lastname: Skinner
authors.forename: S
authors.initials: S
authors.lastname: Yousif
authors.forename: R R
authors.initials: RR
authors.lastname: Davis
authors.forename: J P
authors.initials: JP
authors.lastname: Gregg
authors.forename: M
authors.initials: M
authors.lastname: Sivak
authors.forename: T H
authors.initials: TH
authors.lastname: Konia
authors.forename: K
authors.initials: K
authors.lastname: Thomas
authors.forename: R L
authors.initials: RL
authors.lastname: Wollmann
mesh_terms: D003241:Consanguinity; D016110:Epidermolysis Bullosa Simplex / Q000150:complications / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D016254:Mutagenesis, Insertional / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000503:physiopathology; D010375:Pedigree; D051190:Plectin / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: C504423:CHRNE protein, human; C495332:PLEC protein, human; D051190:Plectin; D011978:Receptors, Nicotinic