Alternative titles; symbols
HGNC Approved Gene Symbol: ADGRV1
Cytogenetic location: 5q14.3 Genomic coordinates (GRCh38) : 5:90,558,797-91,164,437 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q14.3 | ?Febrile seizures, familial, 4 | 604352 | Autosomal dominant | 3 |
| Usher syndrome, type 2C | 605472 | Autosomal recessive; Digenic dominant | 3 | |
| Usher syndrome, type 2C, GPR98/PDZD7 digenic | 605472 | Autosomal recessive; Digenic dominant | 3 |
ADGRV1 is a large G protein-coupled receptor (GPCR) that is expressed ubiquitously and plays important roles in the sensory and central nervous system (CNS). In the inner ear, ADGRV1 and several other proteins form the ankle-link complex (ALC), which is involved in hair-cell development (summary by Guan et al., 2023).
By screening for cDNAs with the potential to encode large proteins expressed in brain, Ishikawa et al. (1998) isolated a partial cDNA encoding GPR98, which they called KIAA0686. The deduced 326-amino acid protein was predicted to be related to rat latrophilin (see NRXN1; 600565).
Using anchored PCR techniques to extend a cDNA containing sequence for a GPCR transmembrane (TM) segment, followed by RT-PCR and screening of BAC and YAC clones, Nikkila et al. (2000) isolated a cDNA encoding VLGR1. Sequence analysis predicted that the 1,967-amino acid VLGR1 protein contains an N-terminal signal peptide, 7 putative Na(+)/Ca(2+) exchangers, 21 N-linked glycosylation sites, the TM region, and a C-terminal domain with a palmitoylation site and multiple potential serine phosphorylation sites. Northern blot analysis of adrenal and testis RNA revealed faint expression of fragmented transcripts; no expression was detected in liver. RT-PCR analysis detected low but wide expression in normal tissues except liver, spleen, and leukocytes. Calcium overlay binding analysis indicated that the extracellular repeat domains bind Ca(2+). The binding was not inhibited by magnesium, but it was inhibited by neomycin and by gadolinium. Western blot analysis showed expression of an approximately 220-kD cell surface VLGR1 protein. Nikkila et al. (2000) proposed that VLGR1 binds its ligand through calcium-mediated interactions.
By in situ hybridization analysis, McMillan et al. (2002) demonstrated high expression of mouse Vlgr1 in the neural groove by embryonic day 8.0 and in the neuroepithelium by embryonic day 8.5, particularly in the ventral developing floor of the brain. As gestation progressed, expression became most intense in optical structures and extended throughout the brain before narrowing with the slowing of neurogenesis in late gestation. In adult mice, expression was restricted to the mammillary nuclei of the hypothalamus. By RT-PCR analysis of mouse brain tissue, followed by 5-prime and 3-prime RACE amplifications and human genome database analysis, McMillan et al. (2002) isolated cDNAs encoding 2 isoforms of VLGR1. They designated these isoforms VLGR1B and VLGR1C and renamed the isoform identified by Nikkila et al. (2000) VLGR1A. The deduced 6,307-amino acid VLGR1B protein contains a putative signal peptide, 90 predicted N-linked glycosylation sites, 35 calcium exchanger (CALX)-beta repeats, and a potential pentraxin (PTX; see 602492) domain in its extracellular portion. The TM segment of VLGR1B is related to rat latrophilin. The deduced 2,296-amino acid VLGR1C protein has a signal peptide, 15 CALX-beta domains, and the PTX domain, but it has no TM segments. RT-PCR analysis suggested that VLGR1B is 4 times more abundant than VLGR1A in all tissues tested, whereas VLRG1C is approximately 1.5 times more abundant than VLGR1B in most tissues tested; in fetal testis, VLGR1C was expressed almost exclusively. McMillan et al. (2002) concluded that VLGR1 is the largest protein expressed on the cell surface and is probably a marker for a neural progenitor cell type and important for development of the CNS. They noted that Vlgr1b predominates in the mouse and that there is no murine homolog of human VLGR1A.
By genomic sequence analysis, McMillan et al. (2002) determined that the GPR98 gene contains 90 exons and spans at least 600 kb.
Using radiation hybrid analysis, Ishikawa et al. (1998) mapped the GPR98 gene to chromosome 5. By linkage analysis of YAC clones, FISH, and radiation hybrid analysis, Nikkila et al. (2000) mapped the GPR98 gene to chromosome 5q14.1.
Skradski et al. (2001) identified a genomic clone containing the human homolog of the mouse Mass1 gene. Using this clone for fluorescence in situ hybridization, they mapped the human GPR98 gene to chromosome 5q14.
Most genes mutated in hereditary idiopathic epilepsies encode subunits of ion channels. Two apparent exceptions to this rule are the MASS1 gene, and the LGI1 (604619) gene, which is mutated in autosomal dominant partial epilepsy with auditory features (ADLTE; 600512). Scheel et al. (2002) determined by amino acid analysis of both proteins that each contains a novel homology domain consisting of a 7-fold repeated 44-residue motif. The architecture and structural features of this new domain make it a likely member of the growing class of protein interaction domains with a 7-bladed beta-propeller fold. In the MASS1 gene product, which is a fragment of the very large G protein-coupled receptor VLGR1, this EAR domain (for epilepsy-associated repeat) is part of the ligand-binding ectodomain. LGI1, as well as a number of newly-identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The human genome encodes at least 6 EAR proteins, some of which map to chromosomal regions associated with seizure disorders. The authors hypothesized that the EAR domain may play an important role in the pathogenesis of epilepsy, either by binding to an unknown antiepileptic ligand or by interfering with axon guidance or synaptogenesis.
Ebermann et al. (2010) performed a yeast 2-hybrid screen of human fetal brain and observed interaction of the PDZ2 domain of the PDZD7 gene (612971) with the C-terminal intracellular domain of GPR98, including its PDZ-binding motif. Coimmunoprecipitation studies confirmed the interaction and revealed that it is mediated by the PDZ2 domain of PDZD7 and the PDZ-binding motif of GPR98.
Familial Febrile Seizures 4
Studies in developed nations indicated that 2 to 5% of all children will experience a febrile seizure before 5 years of age. In the Japanese population, the incidence was calculated to be as high as 7%. A naturally occurring mutation of the Mass1 gene was reported in the Frings mouse strain, which is prone to audiogenic seizures (Skradski et al., 1998; Skradski et al., 2001). The human ortholog, MASS1, maps to 5q14, where a form of febrile seizures (FEB4; 604352) had been mapped. Therefore, MASS1 was a strong candidate for the FEB4 gene. Nakayama et al. (2002) screened for MASS1 mutations in individuals from 48 Japanese families with familial febrile seizures and found 25 DNA alterations. None of 9 missense polymorphic alleles were significantly associated with febrile seizures; however, a ser2652-to-ter mutation (S2652X; 602851.0001) causing a deletion of the C-terminal 126 amino acid residues was identified in 1 family with febrile and afebrile seizures.
In a 20-month-old girl and her mother with febrile seizures, Han et al. (2020) identified a heterozygous missense mutation in the ADGRV1 gene (NM_032119.3, c.2039A-G, D680G, rs547076322). The mutation was identified by targeted exome sequencing and confirmed by Sanger sequencing. The variant had an allele frequency of 2.8 x 10(-5) in the gnomAD database. No functional studies were performed. The authors concluded that the mutation may be a cause FEB4.
Usher Syndrome Type IIC
Usher syndrome type II is a genetically heterogeneous autosomal recessive disorder characterized by hearing loss and retinitis pigmentosa. Type IIC Usher syndrome (USH2C; 605472) maps to 5q14-q21. Weston et al. (2004) considered the VLGR1 gene a likely candidate for USH2C because of its position in the 5q14.3-q21.1 interval, its protein motif structure, and EST representation from both cochlear and retinal subtracted libraries. Using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of PCR products amplified from genetically independent patients with USH2C and 156 other patients with USH2, Weston et al. (2004) identified 4 isoform-specific VLGR1 mutations in 3 families with USH2C and in 2 sporadic cases. All patients with VLGR1 mutations were female, a significant deviation from random expectations. VLGR1 mutations had been identified in both humans and mice, in association with a reflex-seizure phenotype in both species. Three VLGR1 mRNA isoforms are expressed in the human: VLGR1a, VLGR1b, and VLGR1c. The USH2C mutations observed by Weston et al. (2004) all involved isoform VLGR1b, but not isoform VLGR1c.
In 10 of 31 French USH2 patients who were not linked to the USH2A locus (608400), Besnard et al. (2012) identified mutations in the GPR98 gene. In 2 of the 10 patients, only 1 deleterious mutation was identified in GPR98; screening for large genomic rearrangements revealed a large duplication involving several exons of GPR98 in 1 of the patients. In the other patient, the PDZD7 gene (612971) was analyzed, but no mutations were found. Besnard et al. (2012) concluded that GPR98 mutations account for a small but significant proportion of mutations causing USH2 (6.4%).
Usher Syndrome Type IIC, GPR98/PDZD7 Digenic
In a 51-year-old German man with type II Usher syndrome, who was negative for mutation in the Usher genes USH2A (608400), WHRN (607928), and CLRN1 (606397), Ebermann et al. (2010) identified a heterozygous frameshift mutation in the GPR98 gene (602851.0010) and a heterozygous frameshift mutation in the PDZD7 gene (612971.0002). No second mutant allele was detected in GPR98 or PDZD7.
Skradski et al. (1998) mapped a genetic locus causing audiogenic seizures in mice to an interval of approximately 3.6 cM in the middle of mouse chromosome 13. Frings audiogenic seizure-susceptibility mice represent a model for sensory-evoked reflex seizures. Their seizure phenotype is characterized by wild running, loss of righting reflex, tonic flexion, and tonic extension in response to high-intensity sound stimulation. Skradski et al. (2001) identified the Mass1 gene in mutant Frings mice and determined that they were homozygous for a single basepair deletion that led to premature termination of the encoded protein. The mRNA levels of this gene in various tissues were so low that the cDNA eluded detection by standard library screening approaches.
McMillan et al. (2002) noted that the phenotype of the Frings mouse results from a naturally occurring deletion of nucleotide 6835 (G) within exon 31 of the Vlgr1 gene, converting val2250 to a stop codon (V2250X). The mutation prevents the synthesis of Vlgr1b and truncates Vlgr1c by 63 amino acids. The gene reported to be mutant in Frings mouse, Mass1, has several transcripts, the longest of which actually consists of exons 6 to 39 of Vlgr1. McMillan et al. (2002) determined that Mass1 transcripts are expressed, if at all, at low levels compared with Vlgr1. They proposed that the Mass1 mutation in the Frings mouse strain supports the role of VLGR1 in the normal development of the CNS.
Johnson et al. (2005) determined that the V2250X mutation in the mouse Mass1 gene is responsible for the early-onset hearing impairment of BUB/BnJ mice. They also showed that an additive effect of a Cdh23 (605516) mutation causes an age-related progression of the hearing loss.
Guan et al. (2023) generated mice homozygous for a 19-bp deletion in the Adgrv1 gene, which they called the Y6236fsX1 mutation, resulting in a truncated Adgrv1 protein lacking the C-terminal 63 amino acids. Y6236fsX1 corresponds to the human ADGRV1 mutation Y6244fsX1 (602851.0005), which is associated with sensorineural hearing loss and retinitis pigmentosa. Homozygous Adgrv1 Y6236fsX1 mice were viable and had normal body weight, motor function, and life expectancy, but they were profoundly deaf. Immunostaining showed that Y6236fsX1 affected trafficking of Adgrv1 to the stereocilia of cochlear hair cells. Stereocilia of mutant mice became progressively disorganized, impairing the mechanoelectrical transduction function of hair cells. The authors found that Adgrv1 stabilized Ush2a (608400), a component of the ALC, by forming an Adgrv1-Whrn (607928)-Ush2a complex and inhibiting constitutive degradation of Ush2a via a ubiquitin-lysosomal pathway. However, this ability of Adgrv1 was largely abolished in mutant mice, because mutant Adgrv1 lost its ability to inhibit Whrn phosphorylation, which regulated Ush2a ubiquitination by recruiting Wdsub1 (620802). Wdsub1 acted as an intermediary regulator between Whrn and Ush2a, whereas Whrn acted as a scaffold for both Ush2a and Wdsub1 to facilitate regulation of Ush2a ubiquitination levels by Wdsub1. Further analysis provided insights into the architectural organization of the ALC and interaction motifs within the complex at single-residue resolution.
In a Japanese sister and brother (family FS17) with febrile and afebrile seizures (FEB4; 604352), Nakayama et al. (2002) identified a heterozygous c.7955C-to-A transversion in the MASS1 (ADGRV1) gene that resulted in a ser2652-to-ter (S2652X) mutation and deletion of the C-terminal 126 amino acid residues of the protein. The family was 1 of 48 Japanese families with familial febrile seizures that showed evidence of linkage to chromosome 5q14 in which Nakayama et al. (2002) found 25 DNA alterations in the MASS1 gene. None of 9 missense polymorphic alleles were significantly associated with febrile seizures. The father of the sibs carried the mutation but was reported to be unaffected; his sister had a history of febrile and afebrile seizures but declined to be examined.
In a family with Usher syndrome type IIC (USH2C; 605472), Weston et al. (2004) found compound heterozygosity for a c.6901C-T transition (Q2301X) and a 4-bp insertion, c.8716_17insAACA (Ile2906fs) in the ADGRV1 gene. The Q2301X mutation was also found in 2 unrelated patients with sporadic USH2.
For discussion of the 4-bp insertion in the GPR98 gene (8716_17insAACA) that was found in compound heterozygous state in a family with Usher syndrome type IIC (USH2C; 605472) by Weston et al. (2004), see 602851.0002.
In affected members of a family with Usher syndrome type IIC (USH2C; 605472), Weston et al. (2004) found a 1-bp deletion, c.8790delC (Met2931fs), on the maternal allele of the ADGRV1 gene.
In affected members of a family with Usher syndrome type IIC (USH2C; 605472), Weston et al. (2004) found a 19-bp deletion, c.18732_18750del19bp (Thr6244Ter), on the paternal allele of the ADGRV1 gene.
In affected members of a large consanguineous Tunisian family with Usher syndrome type IIC (USH2C; 605472), Hmani-Aifa et al. (2009) identified a homozygous c.18131A-G transition in exon 85 of the GPR98 gene, resulting in a tyr6044-to-cys (Y6044C) substitution in a highly conserved residue in the second extracellular loop. The mutation was predicted to disrupt an interloop disulfide bridge, leading to an improperly folded loop and nonfunctional receptor. Heterozygous mutation carriers were unaffected. The family also segregated nonsyndromic retinitis pigmentosa-40 (RP40; 613801), caused by a homozygous mutation in the PDE6B gene (180072.0007). One family member who was doubly homozygous for both mutations had a more severe ocular phenotype. Two family members who were doubly heterozygous for both mutations were unaffected at ages 82 and 65 years, respectively. Hmani-Aifa et al. (2009) commented that consanguinity can increase familial clustering of multiple hereditary diseases within the same family. The family had originally been reported by Hmani et al. (1999).
In affected members of a large consanguineous Iranian family with Usher syndrome type IIC (USH2C; 605472), Hilgert et al. (2009) identified a large homozygous 136-kbp deletion in the GPR98 gene, resulting in the deletion of exons 84 and 85 and premature protein termination. Three males and 3 females were affected. Two family members with only hearing loss did not carry the deletion, suggesting a different cause of hearing loss in these individuals.
In a German brother and sister with Usher syndrome type IIC (USH2C; 605472), Ebermann et al. (2009) identified compound heterozygosity a 13-bp deletion (2258_2270del13) in exon 12 of the GPR98 gene and a 2-bp deletion (5356_5357delAA; 602851.0009) in exon 25 of the GPR98 gene. Both mutations resulted in frameshift and premature termination and were not found in 50 healthy controls. The patients were 43 and 50 years old, respectively, at the time of the examination. Both patients had congenital, bilateral, symmetric, moderate to severe hearing loss with a mildly downsloping pure tone audiogram. The woman had slightly better visual acuity and had later onset of visual defects than her brother, but both had retinitis pigmentosa. Ebermann et al. (2009) concluded that males and females with GPR98 mutations show a typical USH2C phenotype.
For discussion of the 2-bp deletion in the GPR98 gene (5356_5357delAA) that was found in compound heterozygous state in a brother and sister with Usher syndrome type IIC (USH2C; 605472) by Ebermann et al. (2009), see 602851.0008.
In a 51-year-old German man with Usher syndrome type IIC (USH2C; 605472), Ebermann et al. (2010) identified a heterozygous 1-bp deletion (17137delG) in the GPR98 gene and a heterozygous frameshift mutation in the PDZD7 gene (612971.0002). No second mutant allele was detected in GPR98 or PDZD7. His unaffected sister was heterozygous for the PDZD7 mutation but did not carry the GPR98 mutation, which was also not found in 50 controls.
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