LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner

Bisei Ohkawara, Macarena Cabrera-Serrano, Tomohiko Nakata, Margherita Milone, Nobuyuki Asai, Kenyu Ito, Mikako Ito, Akio Masuda, Yasutomo Ito, Andrew G Engel, Kinji Ohno

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.

Original languageEnglish (US)
Pages (from-to)1856-1868
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2014
Externally publishedYes

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Congenital Myasthenic Syndromes
Agrin
Mutation
Neuromuscular Junction
LDL-Receptor Related Proteins
Exome
Post-Synaptic Density
Membranes
LDL Receptors
Bone Diseases
beta Catenin
Maintenance
Safety
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

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LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. / Ohkawara, Bisei; Cabrera-Serrano, Macarena; Nakata, Tomohiko; Milone, Margherita; Asai, Nobuyuki; Ito, Kenyu; Ito, Mikako; Masuda, Akio; Ito, Yasutomo; Engel, Andrew G; Ohno, Kinji.

In: Human Molecular Genetics, Vol. 23, No. 7, 01.04.2014, p. 1856-1868.

Research output: Contribution to journalArticle

Ohkawara, Bisei ; Cabrera-Serrano, Macarena ; Nakata, Tomohiko ; Milone, Margherita ; Asai, Nobuyuki ; Ito, Kenyu ; Ito, Mikako ; Masuda, Akio ; Ito, Yasutomo ; Engel, Andrew G ; Ohno, Kinji. / LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 7. pp. 1856-1868.
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AU - Nakata, Tomohiko

AU - Milone, Margherita

AU - Asai, Nobuyuki

AU - Ito, Kenyu

AU - Ito, Mikako

AU - Masuda, Akio

AU - Ito, Yasutomo

AU - Engel, Andrew G

AU - Ohno, Kinji

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