In a 17-year-old girl with congenital myasthenic syndrome-17 (CMS17; 616304), Ohkawara et al. (2014) identified compound heterozygous missense mutations in the LRP4 gene: a c.3697G-A transition (chr11.46,897,357G-A, GRCh37), resulting in a glu1233-to-lys (E1233K) substitution, and a c.3830G-A transition, resulting in an arg1277-to-his (R1277H; 604270.0012) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 137) database. The E1233K mutation was present in the patient's unaffected father; DNA from the mother was unavailable. Both substitutions occurred at conserved residues in the third beta-propeller domain of the protein, and were located on the edge of the fifth and sixth blades, respectively. In vitro functional expression studies showed that both mutations decreased binding affinity of LRP4 for agrin (AGRN; 103320) and MuSK (601296) and did not enhance downstream activation of the MuSK signaling pathway, thus impairing clustering of acetylcholine receptors (AChRs). Neither mutation had an effect on WNT (164820) signaling. Patient skeletal muscle biopsy showed type 1 fiber predominance and irregularly arrayed synaptic contacts that varied in shape and size. Electron microscopy showed that the size of the nerve terminals was reduced to 60% and that of the postsynaptic region to 48%. There was normal expression of the AChR and acetylcholinesterase (AChE; 100740), although the total number of AChRs per endplate was slightly decreased.
