Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ROBO1
Cytogenetic location: 3p12.3 Genomic coordinates (GRCh38): 3:78,597,239-79,767,998 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p12.3 | ?Nystagmus 8, congenital, autosomal recessive | 257400 | Autosomal recessive | 3 |
| Neurooculorenal syndrome | 620305 | Autosomal recessive | 3 | |
| Pituitary hormone deficiency, combined or isolated, 8 | 620303 | Autosomal dominant | 3 |
The ROBO1 gene encodes a receptor that is a member of the neural cell adhesion molecule (NCAM; 116930) family of receptors. ROBO1 acts as an axon guidance receptor that defines a novel subfamily of immunoglobulin superfamily proteins that is highly conserved from fruit flies to mammals (Kidd et al., 1998).
Kidd et al. (1998) identified the Drosophila roundabout (robo) gene from a large-scale mutant screen for genes that control axonal crossing of the midline of the central nervous system. Using a sequence derived from the Drosophila gene, the authors isolated a the human homolog, termed ROBO1, from a human fetal brain cDNA library. The deduced human ROBO1 protein contains 1,395 amino acids, including 5 immunoglobulin domains, 3 fibronectin III domains, a transmembrane domain, and an intracellular tail. The identity with the Drosophila gene is higher in the immunoglobulin domains (39-59%). Northern blot analysis identified a single 6.4-kb mRNA transcript.
Kidd et al. (1998) cloned a full-length rat Robo1 homolog as well as a partial sequence of a second human homolog, termed ROBO2 (602431). The rat Robo1 protein shares greater than 95% sequence identity with the human ROBO1 protein. Rat Robo1 is expressed in E13 embryos in the dorsal spinal cord in a pattern corresponding to the cell bodies of commissural neurons.
Sundaresan et al. (1998) cloned the ROBO1 gene, which they referred to as DUTT1 (deleted in U Twenty Twenty cells), from a lung cancer tumor suppressor gene region at chromosome 3p12. The gene mapped within a region of overlapping homozygous deletions characterized in both small cell lung cancer lines (SCLC) and in a breast cancer line.
Hannula-Jouppi et al. (2005) found that ROBO1 undergoes complex alternative splicing, and that DUTT1 is 1 of several splice variants. Two additional exons, exons a and 7b, as well as additional sequence to exon 1 were identified. The authors postulated that ROBO1 and DUTT1 may have different functions.
Munch et al. (2022) found expression of the ROBO1 gene in human fetal kidneys, where it localized to the outer nephrogenic zone within comma-shaped bodies and S-shaped bodies, supporting a role for ROBO1 in normal nephrogenesis.
Dallol et al. (2002) determined that the DUTT1 gene contains 29 exons and spans at least 240 kb of genomic sequence. The 5-prime region contains a CpG island, and the poly(A)+ tail has an atypical signal.
Sundaresan et al. (1998) localized the ROBO1 gene to chromosome 3p12.
Drosophila Robo1 mutants show abnormal axonal crossing of the midline in the central nervous system; too many axons cross and recross the midline. Kidd et al. (1998) showed that Drosophila Robo1 was expressed on growth cones of axons in the longitudinal tracts that never crossed the midline, whereas it was low or absent from axons in the commissural tracts. Kidd et al. (1998) concluded that Robo1 functions as a growth cone receptor for a midline repellent that acts as the gatekeeper controlling midline crossing.
Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit (see, e.g., SLIT1, 603742) and simultaneously lose responsiveness to the attractant netrin (601614). These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Stein and Tessier-Lavigne (2001) provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Robo silenced the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC (120470). Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. Note that an expression of concern was published for the article by Stein and Tessier-Lavigne (2001).
Using a variety of mammalian, avian, and Drosophila constructs and cells, Rhee et al. (2002) showed that Robo, activated by Slit, disrupted cell adhesion and neurite outgrowth mediated by N-cadherin (114020). Robo activation was accompanied by tyrosine phosphorylation of beta-catenin (116806) and the loss of beta-catenin from N-cadherin complexes. The result was the formation of a complex between Robo and N-cadherin, uncoupling N-cadherin from its association with the cytoskeleton. The C terminus of Robo mediated these effects. Rhee et al. (2002) concluded that a repulsive cue could be directly converted into decreased traction between the growth cone and the substrate.
Using in situ hybridization analysis, Bagri et al. (2002) detected expression of Robo1 and Robo2 in the developing cortex and thalamus of mouse embryos. They detected a complementary pattern of expression of Robo and Slit genes in the developing mouse forebrain and concluded that these molecules may play a role in the guidance of corticofugal and thalamocortical projections.
Using overexpression and knockdown studies, Yuasa-Kawada et al. (2009) showed that the deubiquitinating enzyme Usp33 (615146) was required for growth cone collapse in response to Slit exposure. Usp33 bound the intracellular domain of Robo1 and stabilized Robo1 against ubiquitination and proteasome-mediated degradation.
Zhou et al. (2013) tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. Zhou et al. (2013) found that intestinal stem cells expressed Slit2 (603746) and its single-span transmembrane cell-surface receptor Robo1. Partial genetic deletion of Robo1 decreased intestinal stem cell numbers and caused villus hypotrophy, whereas a Slit2 transgene increased intestinal stem cell numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin-1 (Rspo1; 609595), a Wnt agonist, plus Slit2 reduced intestinal stem cell loss, mitigated gut impairment, and protected animals from death, without concomitantly decreasing tumor sensitivity to chemotherapy. Therefore, Zhou et al. (2013) concluded that Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.
Combined Pituitary Hormone Deficiency 8
In a girl (P3) and her paternal aunt (P4) (family 3) with combined pituitary hormone deficiency-8 (CPHD8; 620303), Bashamboo et al. (2017) identified a heterozygous missense mutation in the ROBO1 gene (C240S; 602430.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in the girl's father who had short stature, but did not undergo further testing. Exome sequencing identified 2 additional heterozygous frameshift or nonsense variants in the ROBO1 gene in 2 sibs (family 1) and in a sporadic patient (family 2) with isolated GH deficiency and PSIS on brain imaging. However, both variants were inherited from unaffected parents. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated haploinsufficiency as a pathogenetic mechanism.
In a Chinese boy and his mother with CPHD8, Liu and Chen (2020) identified a heterozygous missense mutation in the ROBO1 gene (P564S; 602430.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; functional studies of the variant were not performed.
Neurooculorenal Syndrome
In 2 fetuses and a living male sib (family 1) with variable manifestations of neurooculorenal syndrome (NORS; 620305), Rasmussen et al. (2018) identified compound heterozygous mutations in the ROBO1 gene (S1608X, 602430.0003 and P176S, 602430.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the ExAC or 1000 Genomes Project databases. Each was inherited from one of the unaffected parents. Subsequent sequencing of the ROBO1 gene in a cohort of 8 fetuses with bilateral renal agenesis identified 1 with compound heterozygous mutations in the ROBO1 gene (E1229X and S1608X); this fetus also had hydrocephalus. Functional studies of the variants were not performed.
In a 5-year-old Japanese boy, born of consanguineous parents, with NORS, Dateki et al. (2019) identified a homozygous splice site mutation (c.1342+1G-A; 602430.0005). The mutation was found by exome sequencing; each unaffected parent was heterozygous. Functional studies of the variant were not performed, but the mutation was predicted to cause nonsense-mediated mRNA decay with a loss-of-function. The patient initially came to attention for combined pituitary hormone deficiency and severe global developmental delay, and was later found to have congenital anomalies of the kidney and urinary tract (CAKUT) (Munch et al., 2022).
In 4 children (ID3-ID6) and a man (ID1) with NORS, Munch et al. (2022) identified homozygous or compound heterozygous mutations in the ROBO1 gene (see, e.g., 602430.0006-602430.0008). Three patients had biallelic splice site or nonsense mutations, suggesting a complete loss of ROBO1 function, whereas 2 patients (ID1 and ID4) were compound heterozygous for a nonsense and a missense mutation. In addition, 3 affected fetuses from a French family with the disorder carried compound heterozygous frameshift mutations in the ROBO1 gene. Renal tissue from 1 of the affected fetuses showed severely dysplastic and cystic renal parenchyma as well as an absence of ROBO1 staining. None of the mutations were present in the gnomAD database. None of the heterozygous carrier parents were affected. Noting that heterozygous ROBO1 mutations have been associated with variable phenotypes, Munch et al. (2022) concluded that there is incomplete penetrance for heterozygous mutations and that gene dosage effects may be conferred by distinct variants in the ROBO1 gene.
Autosomal Recessive Congenital Nystagmus 8
In 3 adult brothers, born of consanguineous Turkish parents (family 1, HOU2644), with autosomal recessive congenital nystagmus-8 (NYS8; 257400), Huang et al. (2022) identified a homozygous missense mutation in the ROBO1 gene (S1522L; 602430.0009). The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was found in the gnomAD database in the heterozygous state at a frequency of 0.058% and once in the homozygous state in an individual of African origin. The authors noted that this mild phenotype may have been overlooked or that the variant may show incomplete penetrance. The S1522L variant was less toxic than human wildtype ROBO1 when expressed in Drosophila, suggesting that the S1522L variant is a partial loss-of-function allele.
Associations Pending Confirmation
Dallol et al. (2002) found no inactivating mutations in the ROBO1 gene in lung, breast, and kidney cancers; however, 7 germline missense changes were found. Dallol et al. (2002) identified tumor-specific promoter region methylation of DUTT1 in human breast cancer, renal cell carcinoma, and non-small cell lung cancer. The authors suggested it may act as a tumor suppressor gene.
Hannula-Jouppi et al. (2005) reported a patient with dyslexia and a translocation t(3;8)(p12;q11) that disrupted intron 1 of the ROBO1 gene. He had 1 sib with dyslexia who did not have the translocation. However, in an unrelated large family with dyslexia showing linkage to chromosome 3 (DYX5; 606896), Hannula-Jouppi et al. (2005) identified a specific SNP haplotype that segregated with dyslexia. Comparison of genomic and cDNA samples from 4 dyslexic family members showed that ROBO1 mRNA was only weakly or not at all transcribed from the allele that segregated with dyslexia, whereas biallelic expression was observed in control brain RNA. Repeated measurements showed that the mean expression of the dyslexia-associated allele was 66% of control values. Hannula-Jouppi et al. (2005) suggested that haploinsufficiency for ROBO1 may predispose humans to dyslexia. The authors further suggested that ROBO1 plays a role in neuronal development and that DUTT1 plays a role in tumorigenesis.
Using the 100K SNP scan of the Framingham Heart Study, Lasky-Su et al. (2008) identified an age-varying association between rs1455832, located in intron 1 of the ROBO1 gene, and obesity (unadjusted p = 0.000624): the minor homozygous CC allele showed a gene-age interaction that was associated with increased BMI and diminished after age 45. In follow-up analysis of 8 independent samples comprising 13,584 individuals, the association was replicated in 5 of 8 samples, showing an age-dependent relationship between rs1455832 and BMI. Noting that it is difficult for cross-sectional study designs to detect age-varying associations, Lasky-Su et al. (2008) concluded that important genetic associations may be missed if the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and the statistical analysis strategy.
Kruszka et al. (2017) reported 2 unrelated patients with congenital heart disease associated with de novo heterozygous nonsense variants in the ROBO1 gene identified through exome sequencing of large cohorts. Proband 1 was a 14-year-old Thai boy with tetralogy of Fallot, septal defects, dysmorphic facial features, and normal growth and development associated with a de novo R119X variant. He was part of a cohort of 50 individuals with congenital heart disease who underwent genetic analysis. Proband 2 was an 8-year-old Chinese girl with ventricular septal defect and congenital diaphragmatic hernia associated with a de novo R310X variant. She also had normal growth and development. This patient was ascertained from a cohort of 366 individuals with congenital diaphragmatic hernia who were studied. Both variants were confirmed by Sanger sequencing. Functional studies of the variants were not performed, but the authors postulated a loss-of-function effect.
Huang et al. (2022) reported a 4-year-old Chinese boy (family 2) with epileptic encephalopathy and severe developmental delay associated with a de novo heterozygous missense variant (D422G) in the ROBO1 gene. This variant was not present in population databases, including gnomAD. The boy had onset of infantile spasms at 3 months of age, refractory seizures, inability to stand, and poor eye contact. Brain imaging was normal, and he had no ophthalmologic defects or obvious dysmorphic features. Studies of the orthologous variant (D413G) in Drosophila indicated that it is a loss-of-function allele that showed toxic properties in retinal electrophysiologic studies. D413G also mislocalized to the soma and axon of neurons, which may underlie the toxic effect of the variant.
Zallen et al. (1998) cloned a C. elegans gene, termed sax3, that is homologous to ROBO1. Mutations in sax3 resulted in repeated midline crossing by ventral cord axons that normally do not cross the midline after they join the ventral cord, a phenotype similar to that of Drosophila Robo mutants. Sax3 also appeared to be required for the guidance of some axons to the ventral cord, implicating this gene in 2 different types of axonal guidance events. A sax3/GFP fusion gene was expressed in developing neurons during axon outgrowth, and sax-3 function was required at the time of axon guidance. Zallen et al. (1998) concluded that in C. elegans this gene mediates cell interactions during guidance decisions.
Andrews et al. (2006) found that homozygous Robo1-knockout mice died at birth but prenatally displayed major defects in cortical interneuron migration and axon pathfinding, including dysgenesis of corpus callosum and hippocampal commissure, as well as abnormalities in corticothalamic and thalamocortic targeting. The authors noted that Slit2-knockout and Slit1/Slit2 double-knockout mice show malformations in callosal development and defects in corticothalamic and thalamocortical targeting, as well as optic tract defects. In Slit mutant mice, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. These phenotypes of corticothalamic targeting were not observed in Robo1-knockout mice. Instead, both corticothalamic and thalamocortic axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Up to twice as many interneurons at embryonic day-12.5 (E12.5) and E15.5 migrated into the cortex of Robo1-knockout mice, particularly in both rostral and parietal regions, than in Slit mutants. Andrews et al. (2006) concluded that the distinct phenotypes of Robo1 and Slit mutants suggest that additional genes are likely involved with Slit/Robo signaling.
Kruszka et al. (2017) found that mice homozygous for an ENU-induced missense mutation in the Robo1 gene (I270T) showed craniofacial and cardiac abnormalities. Mutant mice had a shortened snout, micrognathia, and cleft palate. Heart malformations included double outlet right ventricle (DORV) and septal defects. Robo1-null mice showed septal defects as embryos.
Munch et al. (2022) found that mutant mice homozygous for the Robo1 I270T mutation displayed severe urogenital defects consistent with congenital anomalies of the kidney and urinary tract (CAKUT) observed in humans with biallelic ROBO1 mutations. Mutant mice had complete absence of Robo1 expression in the kidney. These authors noted that Robo1 mutant mice have congenital heart defects and craniofacial abnormalities, which are also observed in patients with biallelic ROBO1 mutations.
Huang et al. (2022) found that robo1 in Drosophila was expressed in numerous neurons of the central brain, optic lobe, and peripheral lamina, but rarely in glia. There was broad expression in adult optic neurons, where it plays a role in phototransduction and retinal activity. Complete loss of the robo1 gene in Drosophila caused midline crossing defects of the axon and increased amplitudes of photoreceptors compared to controls. These defects could be rescued by expression of the Drosophila wildtype gene, but not by human ROBO1. In fact, expression of human ROBO1 was toxic to flies, resulting in decreased viability.
In a girl (P4) and her paternal aunt (P5) (family 3) with combined pituitary hormone deficiency-8 (CPHD8; 620303), Bashamboo et al. (2017) identified a heterozygous c.719G-C transversion (c.719G-C, ENST00000464233) in the ROBO1 gene, resulting in a cys240-to-ser (C240S) substitution at a highly conserved residue in the second Ig-like domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in the girl's father who had short stature but did not undergo further testing. The mutation was not present in several public databases, including dbSNP (build 138), ExAC, Exome Variant Server, and 1000 Genomes Project. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to interfere with ROBO1 function. Brain imaging showed pituitary stalk interruption syndrome (PSIS).
In a Chinese boy and his mother with combined pituitary hormone deficiency-8 (CPHD8; 620303), Liu and Chen (2020) identified a heterozygous c.1690C-T transition (c.1690C-T, NM_002941.3) in the ROBO1 gene, resulting in a pro564-to-ser (P564S) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases. Functional studies of the variant and studies of patient cells were not performed. Brain imaging showed pituitary stalk interruption syndrome (PSIS).
In 2 fetuses and a living male sib (family 1) with variable manifestations of neurooculorenal syndrome (NORS; 620305), Rasmussen et al. (2018) identified compound heterozygous mutations in the ROBO1 gene: a c.4823C-G transversion (c.4823C-G, NM_002941.3), resulting in a ser1608-to-ter (S1608X) substitution, and a c.526C-T transition, resulting in a pro176-to-ser (P176S; 602430.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the ExAC or 1000 Genomes Project databases. Each was inherited from one of the unaffected parents. Subsequent sequencing of the ROBO1 gene in a cohort of 8 fetuses with bilateral renal agenesis identified 1 with compound heterozygous mutations in the ROBO1 gene (E1229X and S1608X); this fetus also had hydrocephalus. Functional studies of the variants were not performed. The pregnancies of the 2 affected fetuses (family 1) were terminated due to bilateral kidney agenesis. Their living male sib did not have renal disease, but showed a complex phenotype with delayed psychomotor and social development, mild dysmorphic features (frontal bossing, curled ears, and abnormal retinal arteries), chronic constipation, enuresis, and poor overall growth. Rasmussen et al. (2018) concluded that biallelic ROBO1 variants cause a syndromic disorder with both renal and extrarenal abnormalities, and that there is variable expressivity even within families.
For discussion of the c.526C-T transition (c.526C-T, NM_002941.3) in the ROBO1 gene, resulting in a pro176-to-ser (P176S) substitution, that was found in compound heterozygous state in 2 fetuses and a living male sib with neurooculorenal syndrome (NORS; 620305) by Rasmussen et al. (2018), see 602430.0003.
In a 5-year-old Japanese boy, born of consanguineous parents, with neurooculorenal syndrome (NORS; 620305), Dateki et al. (2019) identified a homozygous G-to-A transition (c.1342+1G-A, NM_002941) in intron 10 of the ROBO1 gene, predicted to result in a splicing defect with exon skipping and a frameshift causing premature termination. The mutation was found by exome sequencing; each unaffected parent was heterozygous. Functional studies of the variant were not performed, but the mutation was predicted to cause nonsense-mediated mRNA decay with a loss-of-function. The patient had combined pituitary hormone deficiency, dysmorphic facial features, strabismus, severe global developmental delay, and brain imaging abnormalities of the pituitary, corpus callosum, pons, and midbrain, although transverse pontine fibers were present. Munch et al. (2022) reported follow-up of this patient (ID2), noting that he also had congenital anomalies of the kidney and urinary tract (CAKUT). Munch et al. (2022) also noted that this mutation was not present in the gnomAD database.
In a 5-year-old boy (ID3), born of consanguineous Turkish parents, with neurooculorenal syndrome (NORS; 620305), Munch et al. (2022) identified a homozygous G-to-T transversion in intron 21 of the ROBO1 gene (c.2882+1G-T, NM_002941.3), predicted to result in a splicing defect and trigger nonsense-mediated mRNA decay. Functional studies of the variant and studies of patient cells were not performed, but the variant was not present in the gnomAD database. The patient had congenital anomalies of the kidney and urinary tract (CAKUT), dysmorphic features, strabismus, developmental delay, dextrocardia, structural brain abnormalities with normal pituitary, and mirror hand movement disorder. The features suggested a disorder of axonal guidance.
In a 10-year-old boy (ID5), born of unrelated Mexican parents, with neurooculorenal syndrome (NORS; 620305), Munch et al. (2022) identified compound heterozygous nonsense mutations in the ROBO1 gene: a c.687C-G transversion (c.687C-G, NM_002941.3), resulting in a tyr229-to-ter (Y229X) substitution, and a c.2758C-T transition, resulting in an arg920-to-ter (R920X; 602430.0008) substitution. The mutations, which were found by trio-based exome sequencing, were each inherited from an unaffected parent. Functional studies of the mutations were not performed, but both were absent from the gnomAD database. The patient had congenital anomalies of the kidney and urinary tract (CAKUT), unilateral renal agenesis, tetralogy of Fallot, global developmental delay, and brain malformations, including agenesis of the corpus callosum.
For discussion of the c.2758C-T transition (c.2758C-T, NM_002941) in the ROBO1 gene, resulting in an arg920-to-ter (R920X) substitution, that was found in compound heterozygous state in a patient with neurooculorenal syndrome (NORS; 620305) by Munch et al. (2022), see 602430.0007.
In 3 adult brothers, born of consanguineous Turkish parents (family 1, HOU2644), with autosomal recessive congenital nystagmus-8 (NYS8; 257400), Huang et al. (2022) identified a homozygous c.4565C-T transition (c.4565C-T, NM_002941) in the ROBO1 gene, resulting in a ser1522-to-leu (S1522L) substitution in the C-terminal cytoplasmic domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was found in the gnomAD database in heterozygous state at a frequency of 0.058% and once in the homozygous state in an individual of African origin. The authors noted that this mild phenotype may have been overlooked or that the variant may show incomplete penetrance. Studies in Drosophila suggested that the S1522L variant is a partial loss-of-function allele, as it was not as toxic as human wildtype ROBO1. The patients had no additional neurologic features and brain imaging was normal.
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