Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans

Mary C. Whitman, Noriko Miyake, Elaine H. Nguyen, Jessica L. Bell, Paola M. Matos Ruiz, Wai Man Chan, Silvio Alessandro Di Gioia, Nisha Mukherjee, Brenda J. Barry, T. M. Bosley, Arif O. Khan, Elizabeth C. Engle

Research output: Contribution to journalArticle

Abstract

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.

Original languageEnglish (US)
Pages (from-to)3113-3125
Number of pages13
JournalHuman molecular genetics
Volume28
Issue number18
DOIs
StatePublished - Sep 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Whitman, M. C., Miyake, N., Nguyen, E. H., Bell, J. L., Matos Ruiz, P. M., Chan, W. M., Di Gioia, S. A., Mukherjee, N., Barry, B. J., Bosley, T. M., Khan, A. O., & Engle, E. C. (2019). Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans. Human molecular genetics, 28(18), 3113-3125. https://doi.org/10.1093/hmg/ddz137