ROBO3

Chr 11

roundabout guidance receptor 3

Also known as: HGPPS, HGPPS1, HGPS, RBIG1, RIG1

NCBI Gene: 64221 ENSG00000154134 UniProt: Q96MS0

The ROBO3 protein is a transmembrane receptor that guides commissural axons across the midline during neural tube development by regulating responses to multiple guidance cues including NELL2, SLIT proteins, and Netrin-1. Mutations cause horizontal gaze palsy with progressive scoliosis, an autosomal recessive disorder with congenital absence of horizontal eye movements and progressive scoliosis due to failure of corticospinal and somatosensory tracts to cross at the medulla. This gene is extremely intolerant to loss-of-function variants, reflecting its critical role in early nervous system development.

ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the Roundabout (ROBO) gene family that controls neurite outgrowth, growth cone guidance, and axon fasciculation. ROBO proteins are a subfamily of the immunoglobulin transmembrane receptor superfamily. SLIT proteins 1-3, a family of secreted chemorepellants, are ligands for ROBO proteins and SLIT/ROBO interactions regulate myogenesis, leukocyte migration, kidney morphogenesis, angiogenesis, and vasculogenesis in addition to neurogenesis. This gene, ROBO3, has a putative extracellular domain with five immunoglobulin (Ig)-like loops and three fibronectin (Fn) type III motifs, a transmembrane segment, and a cytoplasmic tail with three conserved signaling motifs: CC0, CC2, and CC3 (CC for conserved cytoplasmic). Unlike other ROBO family members, ROBO3 lacks motif CC1. The ROBO3 gene regulates axonal navigation at the ventral midline of the neural tube. In mouse, loss of Robo3 results in a complete failure of commissural axons to cross the midline throughout the spinal cord and the hindbrain. Mutations ROBO3 result in horizontal gaze palsy with progressive scoliosis (HGPPS); an autosomal recessive disorder characterized by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to cross the midline in the medulla. [provided by RefSeq, May 2019]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtGaze palsy, familial horizontal, with progressive scoliosis, 1

Clinical highlights

Gene-disease validity (ClinGen)

gaze palsy, familial horizontal, with progressive scoliosis 1 · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.71

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

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