The ROBO3 gene encodes a protein made of 1,386 amino acids. This protein contains a putative extracellular segment with five immunoglobulin-like motifs and three fibronectin-like motifs, a transmembrane segment, and an intracellular segment with three cytoplasmic signaling motifs. ROBO3 is active in the developing spinal cord and in the brainstem. It is important for the normal development of certain nerve pathways in the brain. Also, it plays a critical role in ensuring the motor and sensory nerve pathways crossover in the brainstem. The bundles of axons must cross from one side of the body to the other in the brainstem, which are necessary in the brain and body communication. Defects in this protein are the cause of an autosomal recessive disorder called Horizontal Gaze Palsy with Progressive Scoliois (HGPPS), which affects vision and also causes an abnormal curvature of the spine (scoliosis).
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.
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).
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.
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.
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.
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