Alternative titles; symbolsINTURNED, DROSOPHILA, HOMOLOG OFKIAA1284PDZ DOMAIN-CONTAINING 6; PDZK6HGNC Approved Gene Symbol: INTUCytogenetic location: 4q28.1 ...
Alternative titles; symbols
HGNC Approved Gene Symbol: INTU
Cytogenetic location: 4q28.1 Genomic coordinates (GRCh38): 4:127,623,270-127,726,736 (from NCBI)
INTU is a core subunit of the CPLANE (ciliogenesis and planar polarity effector) complex, which plays an essential role in ciliogenesis (Toriyama et al., 2016).
▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned INTU, which they designated KIAA1284. The deduced 953-amino acid protein contains a PDZ domain. RT-PCR ELISA detected highest expression in kidney, ovary, and fetal brain, intermediate expression in heart, adult brain, liver, lung, and skeletal muscle, and little to no expression in pancreas, spleen, and fetal liver. INTU was expressed in all specific adult brain regions examined with highest levels in amygdala, corpus callosum, caudate nucleus, substantia nigra, subthalamic nucleus, and spinal cord.
By in situ hybridization of Xenopus embryos, Park et al. (2006) found that Xint, the frog homolog of INTU, was expressed in the neural plate during neural tube closure, with subsequent strong expression in the ventral neural tube and in facial mesenchyme.
By radiation hybrid analysis, Nagase et al. (1999) mapped the INTU gene to chromosome 4. By genomic sequence analysis, Park et al. (2006) mapped the INTU gene to chromosome 4q28.
▼ Gene Function
Using tandem affinity purification and mass spectrometry in mouse kidney IMCD3 cells, followed by pull-down and coimmunoprecipitation analyses, Toriyama et al. (2016) identified and characterized a regulatory module that they termed CPLANE (ciliogenesis and planar polarity effector). The core CPLANE complex consisted of Intu, Fuz (610622), and Wdpcp (613580), and these proteins also interacted strongly with Cplane1 (614571) and Rsg1 (CPLANE2). The authors noted that similar interactions had been observed in high-throughput screens of human proteins and are conserved in Drosophila. Intu, Fuz, Wdpcp, Rsg1, and Cplane1 localized around basal bodies in Xenopus multiciliated cells (MCCs). Knockdown experiments showed a complicated hierarchy of functional interactions among the proteins, with Cplane1, which was required for basal body localization of all the CPLANE proteins but Fuz, at the top of the hierarchy. The proteomic data showed that the CPLANE proteins interacted specifically with core and peripheral intraflagellar transport A (IFT-A) complex subunits, but not with IFT-B subunits. In Xenopus MCCs, Cplane1 was required for recruitment of peripheral IFT-A subunits to basal bodies for assembly onto the IFT-A core. Following knockdown of Cplane1 or Wdpcp, IFT-A core particles lacking peripheral proteins were injected into axonemes and underwent normal bidirectional trafficking, whereas IFT-B particles entered axonemes but failed to move in retrograde direction and accumulated. Toriyama et al. (2016) concluded that CPLANE proteins direct basal body recruitment of IFT machinery and are essential for ciliogenesis.
▼ Molecular Genetics
Short-Rib Thoracic Dysplasia 20
In a female infant with short-rib thoracic dysplasia (SRTD20; 617925), Toriyama et al. (2016) identified compound heterozygosity for mutations in the INTU gene: a truncating mutation (E355X; 610621.0001) and a missense mutation (E500A; 610621.0002). In addition, the authors identified a male infant with SRTD and apparent digenic inheritance; the patient was double heterozygous for a truncating mutation in the INTU gene (Q276X; 610621.0003), inherited from his unaffected father, and a missense mutation in the WDR35 gene (W311L; 613602.0013), inherited from his unaffected mother.
Orofaciodigital Syndrome XVII
In a 10-year-old Indian boy with orofaciodigital syndrome (OFD17; 617926), originally reported by Panigrahi et al. (2013), Toriyama et al. (2016) performed exome sequencing and identified homozygosity for a 1-bp deletion in the INTU gene (610621.0004) that was present in heterozygosity in his unaffected parents.
▼ Animal Model
Using an antisense morpholino-oligonucleotide, Park et al. (2006) disrupted Xint expression in Xenopus embryos. Knockdown of Xint disrupted Hedgehog (600725) signaling and caused defects in neural tube closure, including exencephaly, spina bifida, and holoprosencephaly-like features. The authors found that the Hedgehog defect in Xint-deficient embryos was secondary to a failure of ciliogenesis and that Xint and Fuzzy (FUZ; 610622) controlled the assembly of an apical actin network that is essential for the normal orientation of ciliary microtubules. Fluorescence microscopy revealed colocalization of Xint and Dishevelled (601365) at the apical surface of ciliated Xenopus epidermal cells. Park et al. (2006) concluded that Inturned, Fuzzy, and Dishevelled regulate ciliogenesis in Hedgehog-responsive cells through a conserved planar cell polarity (PCP) signaling pathway.
▼ ALLELIC VARIANTS ( 5 Selected Examples):
.0001 SHORT-RIB THORACIC DYSPLASIA 20 WITH POLYDACTYLY (1 patient)
In a female infant (R09-459A) with short-rib thoracic dysplasia with polydactyly (SRTD20; 617925), Toriyama et al. (2016) identified compound heterozygosity for 2 mutations in the INTU gene: a c.1063G-T transversion, resulting in a glu355-to-ter (E355X) substitution, and a c.1499A-C transversion, resulting in a glu500-to-ala (E500A; 610621.0002) substitution. The mutation status of the patient's parents was not reported. Functional analysis demonstrated that the E355X mutant failed to localize to basal bodies when expressed in Xenopus multiciliated cells, and the E500A mutation significantly impaired the ability of the protein to recruit IFT43 (614068).
.0002 SHORT-RIB THORACIC DYSPLASIA 20 WITH POLYDACTYLY (1 patient)
For discussion of the c.1499A-C transversion in the INTU gene, resulting in a glu500-to-ala (E500A) substitution, that was found in compound heterozygous state in a female infant (R09-459A) with short-rib thoracic dysplasia with polydactyly (SRTD20; 617925) by Toriyama et al. (2016), see 610621.0001.
.0003 SHORT-RIB THORACIC DYSPLASIA 20/7 WITH POLYDACTYLY, DIGENIC (1 patient)
In a male infant (R04-176A) with short-rib thoracic dysplasia-20 (SRTD20; 617925), Toriyama et al. (2016) identified double heterozygosity for mutations in the INTU and WDR35 (613602) genes. The INTU mutation was a c.826C-T transition, resulting in a gln276-to-ter (Q276X) substitution, and the WDR35 mutation was a missense mutation (W311L; 613602.0013) that had previously been reported in a female infant with SRTD7 (614091). The proband's unaffected parents were each heterozygous for one of the mutations.
.0004 OROFACIODIGITAL SYNDROME XVII (1 patient)
INTU, 1-BP DEL, 396T
In a 10-year-old Indian boy with orofaciodigital syndrome-17 (OFD17; 617926), Toriyama et al. (2016) identified homozygosity for a 1-bp deletion (c.396delT) in the INTU gene, causing a frameshift predicted to result in a premature termination codon (Asn132LysfsTer11). The deletion was present in heterozygosity in his unaffected parents.
.0005 VARIANT OF UNKNOWN SIGNIFICANCE
This variant is classified as a variant of unknown significance because its contribution to nephronophthisis has not been confirmed.
In a 13-year-old girl of Arab ancestry with growth retardation and end-stage renal disease due to nephronophthisis (see NPHP1, 256100), Toriyama et al. (2016) identified homozygosity for a c.1354G-A transition in the INTU gene, resulting in an ala452-to-thr (A452T) substitution at a nonconserved residue. Her unaffected parents and an unaffected sister were heterozygous for the mutation. Functional analysis was not reported, but the authors suggested that A452T might represent a hypomorphic allele.