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INTRAFLAGELLAR TRANSPORT 81; IFT81

INTRAFLAGELLAR TRANSPORT 81; IFT81

Alternative titles; symbolsINTRAFLAGELLAR TRANSPORT 81, CHLAMYDOMONAS, HOMOLOG OFCARNITINE DEFICIENCY-ASSOCIATED GENE EXPRESSED IN VENTRICLE 1; CDV1Other entitie...

Alternative titles; symbols

  • INTRAFLAGELLAR TRANSPORT 81, CHLAMYDOMONAS, HOMOLOG OF
  • CARNITINE DEFICIENCY-ASSOCIATED GENE EXPRESSED IN VENTRICLE 1; CDV1

Other entities represented in this entry:

  • CDV1-RELATED, INCLUDED; CDV1R, INCLUDED

HGNC Approved Gene Symbol: IFT81

Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38): 12:110,124,334-110,218,792 (from NCBI)

▼ Description
The IFT81 gene encodes a core component of the intraflagellar transport (IFT)-B complex, which is involved in anterograde transport from the base to the tip of the cilium (summary by Perrault et al., 2015).

▼ Cloning and Expression
Masuda et al. (1997) identified a novel downregulated gene in the hypertrophied ventricle of juvenile visceral steatosis (JVS) mice by mRNA differential display analysis and termed it carnitine deficiency-associated gene expressed in ventricle-1 (CDV1). They found that CDV1 mRNA is expressed only in the heart, including ventricle and auricle, of control mice; its expression is suppressed in the hypertrophied ventricle of carnitine-deficient JVS mice, but not in the auricle, which is not hypertrophied, suggesting that CDV1 is highly related to heart function or morphology and plays a role in cardiac hypertrophy caused by carnitine deficiency. Masuda et al. (1997) also identified a related gene, which they designated CDV1R, which is expressed more widely and is not affected in carnitine deficiency. The CDV1 cDNA encodes a deduced protein of 107 amino acids, which composed the C-terminal portion of the CDV1R protein consisting of 414 amino acids.

▼ Gene Structure
Higashi et al. (2000) isolated the CDV1/1R gene from a mouse genomic library and found that the gene contains at least 19 exons and encompasses approximately 48 kb. The splice sites conformed to the GT-AG rule, and the CDV1R mRNA containing 19 exons is processed. CDV1 mRNA containing 5 exons was constructed from the 3-prime half of CDV1R. The first exon of CDV1 consists of the 3-prime side (116 bp) of intron 14 and exon 15 (87 bp) of CDV1R. The presumed promoter sequence for CDV1, located in intron 14 of CDV1R, contains the common TATA box and consensus binding sites for various transcription factors that seem to play roles in the heart-specific expression and carnitine deficiency-associated suppression of CDV1. The authors thus showed that 2 mRNA species, CDV1 and CDV1R, are expressed tissue specifically by using promoters peculiar to each transcript in a single gene.

▼ Gene Function
Bhogaraju et al. (2013) found that the 2 core IFT proteins IFT74 (608040) and IFT81 form a tubulin-binding module and mapped the interaction to a calponin homology domain of IFT81 and a highly basic domain in IFT74. Knockdown of IFT81 and rescue experiments with point mutants showed that tubulin binding by IFT81 was required for ciliogenesis in human cells.

▼ Mapping
By interspecific backcross analysis, Higashi et al. (2000) mapped the CDV1/1R gene close to D5MIT68 on mouse chromosome 5, a region corresponding to human chromosome 12q24.

▼ Molecular Genetics
In 2 unrelated male infants with short-rib thoracic dysplasia with or without polydactyly (SRTD19; 617895), Duran et al. (2016) performed exome sequencing and identified compound heterozygosity for mutations in the IFT81 gene (605489.0003-605489.0006).

Using targeted copy number variant screening, Pettersson et al. (2018) identified a homozygous tandem duplication of exons 9 and 10 of the IFT81 gene (605489.0007) in a boy with a mild form of SRTD19. Clinical exome sequencing was negative for any disease-causing variants. The 16.9-kb intragenic duplication, inherited from heterozygous unaffected parents, was predicted in silico to cause premature termination of the protein with a shortening of the IFT81 protein to about half its normal length. Western blot analysis detected a shorter isoform of IFT81 in fibroblasts, but no wildtype IFT81 protein. Studies in zebrafish showed that the IFT81 duplication resulted in the loss of a specific splice isoform.

Associations Pending Confirmation

For discussion of a possible association between nephronophthisis-related ciliopathies (NPHP-RC) (see, e.g., NPHP1, 256100) and variation in the IFT81 gene, see 605489.0001 and 605489.0002.

For discussion of a possible association between variation in the IFT81 gene and cone-rod dystrophy, see 120970.

▼ ALLELIC VARIANTS ( 7 Selected Examples):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE
IFT81, IVS11DS, G-A, +1
This variant is classified as a variant of unknown significance because its contribution to a ciliopathy has not been confirmed.

In a 5-year-old girl (A3286-21), born of consanguineous Egyptian parents, with a phenotype consistent with a nephronophthisis-related ciliopathy (NPHP-RC) (see, e.g., NPHP1, 256100), Perrault et al. (2015) identified a homozygous G-to-A transition in the donor splice site of intron 11 of the IFT81 gene (c.1188+1G-A, NM_014055.3), predicted to result in the in-frame skipping of exon 11. The variant, which was found by candidate gene sequencing of IFT-B complex proteins, was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. The unaffected mother was heterozygous for the mutation; the unaffected father was not tested. Functional studies and studies of patient cells were not performed. The girl had polydactyly, moderate intellectual disability, and NPHP with medullary cysts, although kidney function was preserved; brain imaging was not available and retinal morphology was normal. The patient was 1 of 1,056 individuals with NPHP-related ciliopathies; none of the other individuals carried IFT81 variants.

.0002 VARIANT OF UNKNOWN SIGNIFICANCE
IFT81, 5-BP DEL, NT2015
This variant is classified as a variant of unknown significance because its contribution to a ciliopathy has not been confirmed.

In an 11-year-old boy (NCK033), born of consanguineous Algerian parents, with retinal dystrophy and intellectual disability suggestive of a ciliopathy, Perrault et al. (2015) identified a homozygous 5-bp deletion (c.2015_2019delACCGG, NM_014055.3) in the last exon (exon 19) of the IFT81 gene, resulting in the loss of the stop codon and extension of the predicted protein by 10 residues (Asp672AlafsTer15). The variant, which was identified by targeted resequencing of 1,666 ciliary genes in 572 individuals with various ciliopathies, segregated with the disorder in the family, and was not found in the dbSNP, 1000 Genomes Project, and Exome Variant Server databases. Whole-exome sequencing of the patient identified 9 additional rare homozygous variants, including a G245R mutation in the PPT1 gene (600722), consistent with a diagnosis of neuronal ceroid lipofuscinosis-1 (CLN1; 256730). PPT1 enzyme activity was 5% of controls. The patient's brother was also homozygous for the PPT1 mutation, but heterozygous for the IFT81 variant; he had no overt retinal or neurologic problems at age 4 years. The proband had retinal dystrophy resulting in complete blindness at age 11 years, intellectual disability with speech delay, and an extrapyramidal and pyramidal syndrome with hyperreflexia. Brain imaging showed cerebellar atrophy without the molar tooth sign, as well as periventricular and subcortical white matter abnormalities. Analysis of patient fibroblasts showed decreased numbers of ciliated fibroblasts compared to controls (69.9% compared to 83.9%), and smaller ciliary length compared to controls. However, Western blot analysis indicated that the IFT81 protein was present at levels similar to controls, and immunocytochemistry studies showed proper IFT81 localization at the ciliary tip and base. Patient cells showed increased mRNA expression of the SHH (600725)-effector protein GLI2 (165230), but normal expression of other SHH pathway components; localization of GLI2 was normal in patient cells. Perrault et al. (2015) noted that CLN1 can cause retinal dystrophy and brain lesions, but suggested that the IFT81 variant may have also contributed to the phenotype.

.0003 SHORT-RIB THORACIC DYSPLASIA 19 WITHOUT POLYDACTYLY
IFT81, ARG512TER (rs200335504)
In an African American boy (patient R98-443) who died at age 19 months of respiratory failure due to short-rib thoracic dysplasia without polydactyly (SRTD19; 617895), Duran et al. (2016) identified compound heterozygous mutations in the IFT81 gene: a c.1534C-T transition, resulting in an arg512-to-ter (R512X) substitution, and a c.87G-C transversion, resulting in a leu29-to-phe (L29F; 605489.0004) substitution. The authors noted that both variants were found at low frequency in the ExAC database, and that the L29F substitution occurs at a highly conserved residue. RT-PCR in cultured patient chondrocytes revealed an at least 50% reduction in transcript levels compared to control cells, whereas Western blot analysis showed nearly complete loss of IFT81 in mutant cells, suggesting that the missense mutation destabilizes IFT81. Functional analysis demonstrated that mutant cells produced elongated cilia, had altered hedgehog (see 600725) signaling and increased posttranslational modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. The patient was also heterozygous for a known variant (R867H; rs76726265) in the SRTD-associated gene TTC21B (612014), but RT-PCR and Western blot showed no differences in TTC21B mRNA or protein levels between patient and control chondrocytes, and the mutation appeared to be a polymorphism in the African American population, with an ethnicity-specific allele frequency of 0.006 in the ExAC database.

.0004 SHORT-RIB THORACIC DYSPLASIA 19 WITHOUT POLYDACTYLY
IFT81, LEU29PHE
For discussion of the c.87G-C transversion in the IFT81 gene, resulting in a leu29-to-phe (L29F) substitution, that was found in compound heterozygous state in a male infant with short-rib thoracic dysplasia without polydactyly (SRTD19; 617895) by Duran et al. (2016), see 605489.0003.

.0005 SHORT-RIB THORACIC DYSPLASIA 19 WITH POLYDACTYLY
IFT81, LEU262TER
In a male infant (R13-147A) who died within a few minutes after birth of respiratory failure due to short-rib thoracic dysplasia with polydactyly (SRTD19; 617895), Duran et al. (2016) identified compound heterozygous mutations in the IFT81 gene: a c.785T-G transversion, resulting in a leu262-to-ter (L262X) substitution, and a 3-bp in-frame deletion (c.1303_1305delCTT; 605489.0006), resulting in deletion of a highly conserved leucine residue (Leu435del) within the third coiled-coil domain. Neither variant was found in the ExAC, 1000 Genomes Project, or Exome Variant Server databases.

.0006 SHORT-RIB THORACIC DYSPLASIA 19 WITH POLYDACTYLY
IFT81, 3-BP DEL, 1303CTT
For discussion of the 3-bp in-frame deletion (c.1303_1305delCTT) in the IFT81 gene, resulting in deletion of a highly conserved leucine residue (Leu435del), that was found in compound heterozygous state in a male infant with short-rib thoracic dysplasia with polydactyly (SRTD19; 617895) by Duran et al. (2016), see 605489.0005.

.0007 SHORT-RIB THORACIC DYSPLASIA 19 WITHOUT POLYDACTYLY
IFT81, 16.9-KB DUP
Pettersson et al. (2018) identified a homozygous tandem duplication of exons 9 and 10 of the IFT81 gene (chr9.110,593,351-110,576,466, GRCh37) in a boy with a mild form of short-rib thoracic dysplasia-19 (SRTD19; 617895). Breakpoint PCR with subsequent Sanger sequencing confirmed the 16.9-kb intragenic duplication and showed that it was Alu-mediated. The duplication was predicted in silico to cause premature truncation of the protein with a shortening of the IFT81 protein to about half its normal length. Western blot analysis and studies in zebrafish confirmed loss of a specific splice isoform of IFT81.

Tags: 12q24.11