Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Cells. 2020 Oct 19;9(10):2320. doi: 10.3390/cells9102320.


Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2-regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

Keywords: ADNP; CRISPR/Cas9; NAP; muscular dystrophy; neuromuscular diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • Base Sequence
  • Behavior, Animal
  • Child
  • Female
  • Gait
  • Gene Expression Regulation
  • Gene Knockdown Techniques*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity
  • Muscles / metabolism
  • Muscles / pathology*
  • Muscular Diseases / metabolism*
  • Muscular Diseases / pathology*
  • NIH 3T3 Cells
  • Naphthoquinones
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Physical Conditioning, Animal
  • RNA, Guide, Kinetoplastida / genetics
  • RNA, Guide, Kinetoplastida / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Single-Cell Analysis*
  • Stem Cells / metabolism
  • Wasting Syndrome / metabolism
  • Wasting Syndrome / pathology*


  • 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone
  • ADNP protein, human
  • Adnp protein, mouse
  • Homeodomain Proteins
  • Naphthoquinones
  • Nerve Tissue Proteins
  • RNA, Guide
  • RNA, Messenger