Alternative titles; symbols
HGNC Approved Gene Symbol: AHI1
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38) : 6:135,283,532-135,497,740 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.3 | Joubert syndrome 3 | 608629 | Autosomal recessive | 3 |
AHI1 is a component of a protein complex in the basal body, a ring-like structure that functions in the transition zone at the base of cilia. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (Chih et al., 2012).
By searching databases for sequences similar to mouse and rat Ahi1, Jiang et al. (2002) identified 3 splice variants of human AHI1. Full-length human AHI1 contains at least 1,187 amino acids. Both the rodent and human proteins have 7 WD40 repeats and an SH3 domain, but human AHI1 contains an N-terminal coiled-coil domain not found in the rodent proteins. One of the human AHI1 splice variants encodes a protein lacking the SH3 domain. RT-PCR analysis of Jurkat human T cells identified splice variants exhibiting exon skipping in the 5-prime UTR. Northern blot analysis of mouse tissues detected several Ahi1 splice variants, with highest expression in brain and testis and very low expression in liver.
Ferland et al. (2004) noted that the AHI1 gene contains a coiled-coil domain in its N-terminal 140 amino acids. These amino acids and this domain are entirely missing in the predicted proteins of both mouse and rat, but are present in the predicted proteins of nonhuman primates and other mammals (cow, pig, dog, and cat).
Jiang et al. (2004) found that expression of mouse and human AHI1 was highest in the most primitive types of normal hematopoietic cells and was downregulated during early differentiation. Cells from 28 patients with chronic myeloid leukemia (CML; 608232) showed elevated AHI1 mRNA in all disease phases and at all stages of differentiation, including quiescent CD34 (142230)-positive cells and terminally differentiating cells. In the most primitive CML cells, transcripts of the 2 shorter isoforms of AHI1 were also increased. Although 15 of 16 human lymphoid and myeloid leukemic cell lines showed aberrant control of AHI1 expression, this was not seen in blasts obtained directly from 15 patients with acute Philadelphia chromosome-negative leukemia. Jiang et al. (2004) concluded that downregulation of AHI1 expression is a conserved step in primitive normal hematopoietic cell differentiation and that perturbations in AHI1 expression may contribute to the development of specific types of human leukemia.
Using immunoprecipitation analysis, Sheng et al. (2008) found that Ahi1 bound tightly to Hap1 (600947) in mouse brain lysates. Depletion of either protein reduced the amount of the other, and conversely, overexpression of either protein increased the endogenous level of the other, suggesting Ahi1 and Hap1 stabilize each other. Reduction of either Hap1 or Ahi1 also reduced the level of Trkb (NTRK2; 600456) and Trkb signaling, as indicated by reduced phosphorylation of Erk (see 601795) and Akt (see 164730). Sheng et al. (2008) concluded that HAP1 and AHI1 maintain the level and signaling of TRKB in neurons.
Hsiao et al. (2009) showed that AHI1 regulated formation of the primary nonmotile cilium via its interaction with RAB8A (165040), a small GTPase critical for polarized membrane trafficking. Mouse Ahi1 protein localized to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In mice, RNAi knockdown of Ahi1 expression led to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a was destabilized and did not properly localize to the basal body. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. Hsiao et al. (2009) concluded that the distribution and functioning of RAB8A is regulated by AHI1, not only affecting cilium formation, but also vesicle transport.
Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (614144) in mouse IMCD3 cells and embryonic fibroblasts, Chih et al. (2012) identified several components of the B9d1-containing ciliary complex, including Tmem231 (614949), Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1 (609883), Ahi1, Cc2d2a (612013), and Kctd10 (613421).
By coimmunoprecipitation of transfected HEK293 cells, Tuz et al. (2013) found that AHI1 interacted with NPHP1 (607100) and with HAP1. Gel filtration followed by Western blot analysis confirmed the interactions and suggested that AHI1 and NPHP1 form heterodimers of about 210 kD and heterotetramers of about 430 kD. AHI1 formed 470-kD heterotetramers, but not heterodimers, with HAP1. Tuz et al. (2013) reported that the WD40 repeats of AHI1 interacted with the SH3 domain of NPHP1, and they found that the region between the coiled-coil domain and central WD40 repeat domain of AHI1 bound the N-terminal TATA-binding protein-interacting region of HAP1. Western blot and immunohistochemical analyses of Ahi1 -/- mouse brain showed that loss of Ahi1 reduced Hap1 content overall and eliminated Hap1 staining in the stigmoid body of hypothalamus.
Jiang et al. (2002) determined that the AHI1 gene contains at least 33 exons and spans 213.7 kb. The protein-coding sequence begins in exon 4.
Ferland et al. (2004) identified the AHI1 gene within a locus on chromosome 6q23.2-q23.3 to which Joubert syndrome (608629) had been mapped.
Ferland et al. (2004) carried out a genomewide screen in 3 Saudi Arabian pedigrees from the same geographic region with autosomal recessive Joubert syndrome-3 (JBTS3; 608629). The addition of another Saudi Arabian family and a pedigree from Turkey narrowed the region of shared homozygosity. Pooling of linkage data and lod scores from the 5 pedigrees resulted in a summed multipoint lod score of 8.36 and a maximum 2-point lod score of 6.31 (at recombination fraction = 0.0) at marker D6S1626. Sequencing of candidate genes in the minimal region of linkage identified 3 independent mutations in the AHI1 gene (608894.0001-608894.0003). It is remarkable that Ferland et al. (2004) found homozygosity for 3 different mutations in the AHI1 gene in the 3 Saudi Arabian families living in the same geographic region. No mutation was identified in the Saudi Arabian family from another region or in the Turkish pedigree.
In affected members of 3 consanguineous families with Joubert syndrome, some with cortical polymicrogyria, Dixon-Salazar et al. (2004) identified 1 missense and 2 frameshift mutations in the AHI1 gene. They designated the AHI1 protein Jouberin. The gene is expressed strongly in embryonic hindbrain and forebrain, and the data of Dixon-Salazar et al. (2004) suggested that AHI1 is required for both cerebellar and cortical development in humans. The authors pointed out that in a subset of patients with Joubert syndrome plus nephronophthisis, the phenotype is caused by mutation in the NPHP1 gene (607100.0005). Nephrocystin, the protein encoded by NPHP1, contains an SH3 domain, suggesting that a shared pathway may be involved in these different forms of Joubert syndrome.
Using a combination of haplotype analysis and gene sequencing, Parisi et al. (2006) screened 117 probands with Joubert syndrome for mutations in the AHI1 gene and identified a total of 15 novel and 5 previously identified mutations in 19 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Fourteen of the mutation-positive families were consanguineous, but no single founder mutation was apparent.
Valente et al. (2006) identified 15 different mutations (see, e.g., 608894.0004-608894.0006) in the AHI1 gene in 11 patients from 10 families with Joubert syndrome. These patients accounted for 7.3% of 137 probands with the molar tooth sign and Joubert-related disorders. A phenotype-specific group of Joubert plus retinopathy had an AHI1 mutation frequency of 21.7% (5 of 23 probands). Clinical analysis indicated that AHI1 mutations were not associated with kidney or liver changes. Retinal abnormalities ranged from retinitis pigmentosa to blindness. There were 2 splice site mutations, 1 missense, and 12 truncating mutations, of which 11 were predicted to abolish all of the SH3 domain and all or part of the WD40 domain. In 2 Egyptian sibs (family MTI-229) with Joubert syndrome-3 originally reported by Valente et al. (2006), Elsayed et al. (2015) found that the causative AHI1 mutation was a homozygous missense change (S761L; 608894.0011) rather than a C-terminal deletion (c.3263delGG; 608894.0004). The missense mutation was found by homozygosity mapping and whole-exome sequencing. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes. Expression of the c.3263delGG mutation in zebrafish did not cause any abnormalities, suggesting that the C-terminal SH3 domain of AHI1 is not required for normal development.
Louie et al. (2010) identified a 2488C-T (arg830-to-trp; R830W) hypomorphic SNP in the WD40 repeat domain of the AHI1 gene that was associated with retinal degeneration in patients with nephronophthisis (NPHP; see, e.g., 256100). Among 153 Italian NPHP individuals, the T allele was found at a higher frequency among those with retinal degeneration compared to those without retinal degeneration (25% compared to 1.8%, p = 5.36 x 10(-6)) and to controls, yielding a relative risk of 7.5. The findings were irrespective of the mutations causing NPHP, and suggested that variation in the AHI1 gene may explain some of the variability in retinal phenotypes. A similar association was not observed for 155 patients with Joubert syndrome.
Ingason et al. (2010) noted that the AHI1 gene locus is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Ingason et al. (2010) replicated studies of AHI1 locus markers previously implicated in schizophrenia in a large European sample. Both the replication study and a metaanalysis showed evidence for significant overrepresentation of all tested alleles in patients compared with controls. They stated that the 6q23 region contains 2 other genes, C6orf217 and PDE7B (604645), that may be considered candidates for involvement in the genetic etiology of schizophrenia.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a nonsense and a missense mutation in the AHI1 gene in affected members of 2 families with Joubert syndrome-3 (608894.0008 and 608894.0009, respectively).
Elsayed et al. (2015) determined that 2 variants in the AHI1 gene resulting in truncated proteins at the C terminus and lacking the SH3 domain (c.3263delGG, 608894.0004 and c.3196C-T) did not cause any abnormalities when expressed in zebrafish. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. In addition, Elsayed et al. (2015) reported an unaffected member of a family segregating nonsyndromic hearing loss who carried the c.3196C-T variant in homozygosity. The findings indicated that the C-terminal SH3 domain of AHI1 is not required for normal development. Elsayed et al. (2015) noted the implications for assessing variants in AHI1 that are part of preconception screening panels, and emphasized that even truncating variants identified in known disease genes must undergo stringent functional and segregation analysis before being classified as pathogenic.
In the phylogenetic tree showing AHI1 gene evolution in hominoids, there was, as pointed out by Ferland et al. (2004), evidence of a greater amount of protein change in the human lineage, suggesting a positive evolutionary selection. They suggested that changes in AHI1 may have been important in the evolution of human-specific motor behaviors.
Louie et al. (2010) showed that Ahi1-null mice were runted and showed high mortality with grossly normal brain morphology. Histologic analysis of the retina showed rapid loss of the outer nuclear (photoreceptor) layer and complete absence of both rod and cone outer segments of photoreceptor cilia early postnatally. Apoptotic cell death was apparent by about 3 weeks of age. However, photoreceptor ciliary axonemes were intact and had normal 9 + 0 microtubule doublet configuration. In heterozygous control mice, Ahi1 expression was enriched at the connecting cilium and basal body and overlapped with expression of a Cetn2 (300006) transgene. These results indicated that absence of Ahi1 results in specific defects of outer segment morphogenesis and photoreceptor survival. The defects induced by Ahi1 loss were associated with misaccumulation of and mislocalization of opsin (180380), which contributed to the loss of photoreceptors. Mice doubly mutant for Nphp1 (607100) and Ahi1 showed a more severe phenotype, indicating a dosage-sensitive genetic interaction between Ahi1 and Nphp1 in retinal development.
Lancaster et al. (2009) found that surviving adult (5 months) Ahi1-null mice had smaller kidneys compared to wildtype and showed characteristics of nephronophthisis, including tubular basement membrane abnormalities, interstitial cell infiltrate and fibrosis, and appearance of multiple microcysts and tubular dilatation at about 1 year of age. Proximal tubules of the corticomedullary region were most affected. At 21 months of age, Ahi1-null mice showed renal impairment, with increased urinary protein content and defects in urine-concentrating abilities. However, renal ciliary formation and morphology were normal. Further studies indicated that loss of Ahi1 led to abrogation of basal Wnt (see, e.g., WNT3A; 606359) activity in the adult mouse kidney. In vitro studies showed that the AHI1 protein acts as a positive modulator of the canonical WNT pathway, acting downstream of beta-catenin (CTNNB1; 116806) stabilization. AHI1 was found to directly interact with and play a role in nuclear accumulation of beta-catenin. Ahi1-null mice showed defective repair of renal injury due to a defective WNT response, which resulted in cyst formation. The findings provided an explanation for the late onset of cyst formation, reflecting a gradual accumulation of mild damage and a defect in injury repair.
Lancaster et al. (2011) found that Ahi1-null mice had a hypoplastic cerebellum with an underdeveloped vermis and mildly defective foliation pattern, similar to that observed in Joubert syndrome. Vermian lobules VI and VII appeared fused, whereas lobule V appeared smaller and underdeveloped. Mutant mouse embryos showed a midline fusion defect with expansion of the rhombic roof plate. In wildtype mice, Ahi1 localized to the basal body in cerebellar granule neurons. Cerebellar granule neurons from mutant mice had normal numbers and morphology of cilia, suggesting that Ahi1 is not required for ciliogenesis, but rather functions in ciliary-mediated signaling. Accordingly, there was decreased Wnt activity at the site of hemisphere fusion, accompanied by reduced cellular proliferation at the site of fusion. Treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. The findings implicated a defect in Wnt signaling in the cerebellar midline phenotype that could be overcome with Wnt stimulation.
In a Saudi Arabian kindred, Ferland et al. (2004) found that Joubert syndrome-3 (JBTS3; 608629) segregated with a homozygous nonsense mutation in the AHI1 gene: 1051C-T (arg351 to ter; R351X).
In a Saudi Arabian kindred, Ferland et al. (2004) discovered that Joubert syndrome-3 (JBTS3; 608629) was associated with a homozygous 1303C-T transition in exon 7 of the AHI1 gene that resulted in an arg435-to-ter (R435X) mutation.
In affected members of a Saudi Arabian kindred with Joubert syndrome-3 (JBTS3; 608629), Ferland et al. (2004) found a homozygous 1328T-A transversion in exon 7 of the AHI1 gene, producing a nonconservative val443-to-asp (V443D) amino acid substitution, resulting in a change from a hydrophobic to a polar or charged residue. It was remarkable that 3 different mutations were found in Saudi Arabian pedigrees from the same geographic region.
Tuz et al. (2013) found that AHI1 with the V443D substitution failed to localize at cell-cell junctions and at the basal body of primary cilia when expressed in transfected IMCD3 mouse kidney cells. The mutation caused a slight, but significant, reduction in cilia formation, disrupted association of AHI1 with NPHP1 (607100) and HAP1 (600947), and caused AHI1 protein instability.
This variant, formerly titled JOUBERT SYNDROME-3 based on the report of Valente et al. (2006), has been reclassified based on the findings of Elsayed et al. (2015).
In 2 sibs (family MTI-229) with Joubert syndrome (608629), born of consanguineous Egyptian parents, Valente et al. (2006) identified a homozygous 2-bp deletion (3263delGG) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (fs1103X) in the SH3 domain. The mutation segregated with the disorder in the family. Both sibs had hypotonia, mental retardation, oculomotor apraxia, and retinitis pigmentosa.
In another study of family MTI-229, Elsayed et al. (2015) identified homozygosity for 2 mutations in the AHI1 gene: the c.3263delGG mutation (rs387906269), resulting in a frameshift and premature termination (Trp1088LeufsTer16), as well as homozygosity for a ser761-to-leu (S761L; 608894.0011) substitution at a highly conserved residue in the fourth WD repeat domain. Expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish, suggesting that the S761L substitution is the causative mutation. Elsayed et al. (2015) concluded that the C-terminal SH3 domain of AHI1 is not required for normal development.
In a patient with Joubert syndrome-3 (JBTS3; 608629), Valente et al. (2006) identified a homozygous 1765C-T transition in exon 13 of the AHI1 gene, resulting in an arg589-to-ter (R589X) substitution. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa.
In a patient with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous Italian parents, Valente et al. (2006) identified a homozygous 2168G-A transition in exon 16 of the AHI1 gene, resulting in an arg723-to-gln (R723Q) substitution within a WD40 domain and predicted to disrupt salt bridging in this region. In addition to the classic neurologic signs of the disorder, the patient also had retinitis pigmentosa.
In 2 Pakistani brothers with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous parents, Utsch et al. (2006) identified a homozygous 1-bp insertion (2369insT) in exon 16 of the AHI1 gene, resulting in a frameshift and premature termination. Both boys had cerebellar ataxia, developmental delay, nystagmus, oculomotor apraxia. One developed end-stage renal failure by age 16 years due to nephronophthisis, thus expanding the clinical phenotype.
In a consanguineous family (8500306) in which 3 of 5 children had Joubert syndrome-3 (JBTS3; 608629), characterized by moderate mental retardation, autism spectrum disorder, ataxia, and cerebellar atrophy, Najmabadi et al. (2011) identified a homozygous G-to-A transition at genomic coordinate chr6:135820491 (NCBI36), resulting in an arg329-to-stop (R329X) substitution.
In a family (M332) in which 4 of 8 children of first-cousin parents had Joubert syndrome-3 (JBTS3; 608629), characterized by severe mental retardation and cerebellar hypoplasia, Najmabadi et al. (2011) identified a homozygous C-to-T transition at genomic coordinate chr6:135811263 (NCBI36), resulting in an arg495-to-his (R495H) substitution.
In a daughter of first-cousin Middle Eastern parents, Tuz et al. (2013) identified a homozygous G-to-T transversion at nucleotide 1052 of the AHI1 cDNA, resulting in an arg351-to-leu (R351L) substitution in the region between the coiled-coil domain and WD40 repeat domain of the AHI1 protein. The patient had developmental delay, ataxia, seizures, and classic brain image findings for Joubert syndrome-3 (JBTS3; 608629). When expressed in transfected IMCD3 mouse kidney cells, AHI1 with the R351L substitution failed to localize at cell-cell junctions and at the basal body of primary cilia. The mutation caused a slight, but significant, reduction in cilia formation.
In 2 sibs with Joubert syndrome-3 (JBTS3; 608629), born of consanguineous Egyptian parents and originally reported by Valente et al. (2006), Elsayed et al. (2015) identified a homozygous mutation in exon 17 of the AHI1 gene, resulting in a ser761-to-leu (S761L) substitution at a highly conserved residue in the fourth WD repeat domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Sequencing Project, or Exome Aggregation Consortium databases, or in 1,629 in-house exomes. Functional studies of the S761L variant were not performed, but structural modeling predicted that it would cause detrimental structural changes.
In this family (family MTI-229), Valente et al. (2006) had previously identified a homozygous 2-bp deletion (c.3263delGG; 608894.0004) in exon 25 of the AHI1 gene, resulting in a frameshift and premature termination of the protein (Trp1088LeufsTer16) in the SH3 domain. However, Elsayed et al. (2015) determined that the c.3263delGG variant was not causative of the phenotype; expression of the truncated variant lacking the C-terminal SH3 domain in zebrafish showed that it did not cause any abnormalities. In contrast, morpholinos against the N-terminal domain produced a ciliopathy phenotype in zebrafish. Elsayed et al. (2015) concluded that the C-terminal SH3 domain of AHI1 is not required for normal development.
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Lancaster, M. A., Gopal, D. J., Kim, J., Saleem, S. N., Silhavy, J. L., Louie, C. M., Thacker, B. E., Williams, Y., Zaki, M. S., Gleeson, J. G. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. (Letter) Nature Med. 17: 726-731, 2011. [PubMed: 21623382] [Full Text: https://doi.org/10.1038/nm.2380]
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Sheng, G., Xu, X., Lin, Y.-F., Wang, C.-E., Rong, J., Cheng, D., Peng, J., Jiang, X., Li, S.-H., Li, X.-J. Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. J. Clin. Invest. 118: 2785-2795, 2008. [PubMed: 18636121] [Full Text: https://doi.org/10.1172/JCI35339]
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