Roundabout Guidance Receptor 3

Alternative Names

  • ROBO3
  • RB-Inhibiting Gene 1
  • RBIG1
  • RIG1
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OMIM Number

608630

NCBI Gene ID

64221

Uniprot ID

Q96MS0

Length

16,040 bases

No. of Exons

29

No. of isoforms

2

Protein Name

Roundabout homolog 3

Molecular Mass

148209 Da

Amino Acid Count

1386

Genomic Location

chr11:124,865,431-124,881,470

Gene Map Locus
11q24.2

Description

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. [From RefSeq]

Molecular Genetics

The ROBO3 gene encompasses 28 exons and spans about 16 kb of genomic DNA. Until recently, 24 mutations (nonsense, frameshift, and splicing) in the ROBO3 gene have been described in patients with HGPPS. These mutations result in non-crossing of selected axonal paths in the central nervous system during embryonic development, which are normally subjected to midline crossing.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_022370.4:c.2770_2779+21delUnited Arab EmiratesNC_000011.10:g.124876451_124876481delPathogenicLikely PathogenicGaze Palsy, Familial Horizontal, with Progressive ScoliosisNG_016214.1:g.16043_16073del; NM_022370.4:c.2770_2779+21del; NP_071765.2:p.His924ProfsTer771704392

Other Reports

Arab

In a consanguineous Arab family with HGPPS, Jen et al. (2004) identified homozygosity for a splice donor site mutation in the first position of intron 13 of the ROBO3 gene in which G was converted to A (IVS13+1G>A). This mutation in the Fn3 II domain is expected to result in premature termination of the protein. The mutation was not identified in 93 control samples.

Qatar

A novel 1726 T/C mutation in the ROBO3 gene was identified by Abu-Amero (2013) in an Arab patient living in Qatar affected with familial horizontal gaze palsy with progressive scoliosis (HGPPS).

Saudi Arabia

In a consanguineous Saudi family with HGPPS, Jen et al. (2004) identified homozygosity for a frameshift mutation in exon 23 of the ROBO3 gene, insertion of a G at nucleotide 3325 (3325+1G). This mutation, not identified in 116 control samples, occurred between the CC2 and CC3 domains and is predicted to incorporate novel sequences following CC2 and to result in premature termination of the ROBO3 protein. If stable, the truncated receptor should retain much of the wild-type protein except for the C terminus, where CC3 resides. Therefore, it is possible that CC3 is required for the normal function of ROBO3; alternatively, the frameshift mutation may interfere with protein folding and trafficking. In a second consanguineous Saudi family with HGPPS, Jen et al. (2004) identified homozygosity for a 2113T>C transition in exon 14 of the ROBO3 gene. This resulted in a ser705-to-pro (p.S705P) substitution in the Fn3 II domain of the gene. This mutation was also not identified in 116 control samples.

Khan et al., (2008) describe a 9-year-old girl affected with substituted convergence for horizontal gaze since birth. She presented at birth with congenital, nonprogressive, abnormal eye movements.  She also had asynchronous blinking, conjugate pendular nystagmus, and high myopia. The patient was the fifth child of first-cousin parents. The coding exons in the ROB03 gene were sequenced and a novel homozygous missense p.Pro771Leu (c.2312 CT) mutation in exon 15 was identified in the patient.  The parents and both of her sisters were heterozygous for the same mutation.  This mutation was not found in 50 healthy Saudi individuals and affected an amino acid that is an evolutionarily conserved in several species.

Abu-Amero et al. (2009) reported four consanguineous families of Saudi Arabian origin affected with HGPPS. Each of these families was found to carry different novel mutations in the ROBO3 gene, which were found in homozygous condition in the affected patients and in heterozygous condition in the parents and some of the unaffected siblings. The first family carried a novel missense mutation c.1226T>C, causing a p.W576R in the first Fn3I-like domain in exon 11. The second family carried a c.335G>C, resulting in p.R112P in the first Ig I-like domain in exon 2. The third family with two affected children carried another new c.1379A>G missense mutation causing p.Q460R in the Ig-like domain V of exon 8. The fourth family also had two affected children, and was found to carry a novel single base deletion at nt 571, which resulted in a frameshift involving codon 127 in the Ig II domain of exon 2 with a premature stop codon in exon 4. None of these mutations were found in the control population, comprising of 120 Saudis and 50 Sudanese subjects. All mutations were classified as 'probably damaging' or 'possibly damaging' by Polyphen.

Volk et al. (2011) described four patients with horizontal gaze palsy and progressive scoliosis (aged between 6 months and 13 years), two of them were siblings.  The three consanguineous families were unrelated.  One of the families was of Saudi origin; the patient was a 13 year old boy who presented with a progressive right-curved thoracolumbar scoliosis.  His horizontal eye movements were severely disturbed.  He had left microhypertropia with fusion and motor developmental delay.  Direct sequencing of the ROBO3 gene revealed a homozygous deletion of 31 base pair including the splice donor site of exon 17; resulting in altered splicing.  Both parents were carriers of this mutation. 

Sudan

Abu Amero-et al. (2009) described a consanguineous Sudanese family with one child affected with HGPPS. Sequence analysis of the ROBO3 gene identified a novel missense mutation c.271C>T, which resulted in a p.P91S in the Ig I domain in exon 2. This mutation was homozygous in the patient and heterozygous in the mother. The mutation was not found in the control population, comprising of 120 Saudis and 50 Sudanese subjects. The mutation was rated 'probably damaging' by Polyphen.

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