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COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina


Collagen Q (ColQ) is a key multidomain functional protein of the neuromuscular junction (NMJ), crucial for anchoring acetylcholinesterase (AChE) to the basal lamina (BL) and accumulating AChE at the NMJ. The attachment of AChE to the BL is primarily accomplished by the binding of the ColQ collagen domain to the heparan sulfate proteoglycan perlecan and the COOH-terminus to the muscle-specific receptor tyrosine kinase (MuSK), which in turn plays a fundamental role in the development and maintenance of the NMJ. Yet, the precise mechanism by which ColQ anchors AChE at the NMJ remains unknown. We identified five novel mutations at the COOH-terminus of ColQ in seven patients from five families affected with endplate (EP) AChE deficiency. We found that the mutations do not affect the assembly of ColQ with AChE to form asymmetric forms of AChE or impair the interaction of ColQ with perlecan. By contrast, all mutations impair in varied degree the interaction of ColQ with MuSK as well as basement membrane extract (BME) that have no detectable MuSK. Our data confirm that the interaction of ColQ to perlecan and MuSK is crucial for anchoring AChE to the NMJ. In addition, the identified COOH-terminal mutants not only reduce the interaction of ColQ with MuSK, but also diminish the interaction of ColQ with BME. These findings suggest that the impaired attachment of COOH-terminal mutants causing EP AChE deficiency is in part independent of MuSK, and that the COOH-terminus of ColQ may interact with other proteins at the BL.

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We thank Dr. Robert Fairclough and Dr. David P. Richman for critical reading of the manuscript, Dr. Palmer Taylor from UC-San Diego for AChE clone, and Dr. Mary C. Farach-Carson from Rice University for the HEK cells expressing perlecan domain I, and Dr. Samuel Ignacio Pascual Pascual, Madrid, Spain, for sharing one of his studied families with us. This work was supported by National Institutes of Health grant RO1NS049117-01 to RAM.

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Correspondence to Juan Arredondo or Ricardo A. Maselli.

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Arredondo, J., Lara, M., Ng, F. et al. COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina. Hum Genet 133, 599–616 (2014).

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  • Basal Lamina
  • Alport Syndrome
  • Asymmetric Form
  • Basement Membrane Extract
  • IRDye 800CW