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.