Alternative titles; symbols
HGNC Approved Gene Symbol: PI4KA
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:20,707,691-20,858,811 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | Gastrointestinal defects and immunodeficiency syndrome 2 | 619708 | Autosomal recessive | 3 |
| Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis | 616531 | Autosomal recessive | 3 | |
| Spastic paraplegia 84, autosomal recessive | 619621 | Autosomal recessive | 3 |
The PI4Ka gene encodes phosphatidylinositol (PI) 4-kinase, which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Several forms of mammalian PI 4-kinases have been purified, characterized, and classified into types II and III. The type II enzymes have an apparent molecular mass of approximately 55 kD, are highly stimulated by detergent, and are inhibited by adenosine. The type III enzymes have an apparent molecular mass of greater than 200 kD, are less stimulated by detergent, and are not inhibited by adenosine (summary by Nakagawa et al., 1996).
By PCR and by screening human placenta and fetal brain cDNA libraries, Wong and Cantley (1994) cloned cDNAs encoding a PI 4-kinase, which they named PI4K-alpha. The predicted 854-amino acid protein has a calculated molecular mass of 97 kD. It contains an ankyrin repeat, a lipid kinase unique domain, a pleckstrin-homology domain, and a lipid kinase catalytic domain. PI4K-alpha has high amino acid sequence similarity to the yeast PI 4-kinases STT4 and PIK1; it has less amino acid sequence similarity to the catalytic domains of mammalian and yeast PI 3-kinases (e.g., 171834) and to the yeast TOR family of proteins. The enzymatic properties of PI4K-alpha were characteristic of type II PI 4-kinases. By Northern blot analysis, 7.5- and 3.5-kb PI4K-alpha transcripts were detected in all human tissues examined, with the highest levels in placenta and brain.
Nakagawa et al. (1996) cloned a PI 4-kinase cDNA from a rat brain cDNA library. The C-terminal amino acid sequence of the predicted 2,041-amino acid rat PI 4-kinase is 98% similar to the amino acid sequence of PI4K-alpha, the human PI 4-kinase cDNA described by Wong and Cantley (1994). Northern blot analysis of adult rat tissues detected a 7.8-kb transcript in all tissues examined, except liver. Based on their similar amino acid sequences and mRNA expression patterns, Nakagawa et al. (1996) suggested that PI4K-alpha and the rat PI 4-kinase represent alternatively spliced forms of the same molecule. The N-terminal region of the rat PI 4-kinase, which is absent in PI4K-alpha, contains 2 proline-rich regions and an SH3 domain. Western blot analysis of lysates from transfected mammalian cells indicated that the rat PI 4-kinase has a molecular mass of approximately 230 kD. Nakagawa et al. (1996) found that the rat PI 4-kinase has the enzymatic properties of type III PI 4-kinases. By in situ hybridization, they detected rat PI 4-kinase mRNA in the gray matter of the brain, with expression higher in fetal brain than in adult brain. Immunohistochemistry demonstrated that the protein is associated with the membranes of Golgi vesicles and vacuoles.
Gross (2016) mapped the PI4KA gene to chromosome 22q11.21 based on an alignment of the PI4KA sequence (GenBank AF012872) with the genomic sequence (GRCh38).
Hammond et al. (2012) used a combination of pharmacologic and chemical genetic approaches to probe the function of plasma membrane phosphatidylinositol 4-phosphate (PI4P), most of which was not required for the synthesis or functions of PI(4,5)P2. However, depletion of both lipids was required to prevent plasma membrane targeting of proteins that interact with acidic lipids or activation of the transient receptor potential vanilloid-1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P2, which may be fulfilled by a more general polyanionic lipid requirement.
Chung et al. (2015) had previously found that EFR3B (616797) and TTC7B (620060) were required for targeting of PI4K3A to the plasma membrane. Using cotransfection and immunoprecipitation experiments with HeLa cells, they found that TMEM150A (616757) also interacted with PI4K3A and EFR3B, but not with TTC7B. Overexpression of TMEM150A in HeLa cells accelerated PI4K3A-dependent recovery of PI(4,5)P2 following its agonist-dependent depletion. Chung et al. (2015) concluded that TMEM150A displaces TTC7B from the PI4K3A-EFR3B complex, following initial targeting of PI4K3A to the plasma membrane, and stabilizes PI4K3A.
By proteomic analysis in HeLa cells, Baskin et al. (2016) confirmed that TTC7B, ERF3A (611798), and EFR3B were components of the PI4KIII-alpha complex. They identified FAM126A (610531) or FAM126B (HYCC2) as additional components of the PI4KIII-alpha complex. TTC7B played a central role in bridging PI4KIII-alpha to EFR3B. Moreover, FAM126A bound directly to TTC7B through its N-terminal portion to form a heterodimer, and FAM126A-TTC7B bound to PI4KIII-alpha simultaneously to form a ternary complex. Interaction of PI4KIII-alpha with TTC7B and FAM126A appeared to stabilize the PI4KIII-alpha fold and stimulate catalytic activity. Moreover, FAM126A loss or reduction in mouse or human destabilized and degraded PI4KIII-alpha complex components and affected PI4KIII-alpha complex assembly and PI4KIII-alpha-mediated PtdIns4P synthesis at the plasma membrane.
Neurodevelopmental Disorder With Spasticity, Hypomyelinating Leukodystrophy, And Brain Abnormalities
In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see 616531), Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene (R796X, 600286.0001 and D1854N, 600286.0002). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development. All 3 fetuses were diagnosed in utero with multiple congenital anomalies, and the pregnancies terminated between 16 and 34 weeks' gestation.
In 8 unrelated patients (patients 1-8) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002-600286.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro studies of cells derived from some of the patients indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. None of the patients had 2 complete loss-of-function mutations, suggesting that complete loss of PI4KA would be incompatible with life. The authors concluded that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development.
Verdura et al. (2021) noted that the fetuses reported by Pagnamenta et al. (2015) were compound heterozygous for 2 loss-of-function variants and may represent the most severe end of the phenotypic spectrum resulting from PI4KA mutations. Verdura et al. (2021) pointed out that among their patients, no abnormalities were detected during pregnancy. Although Verdura et al. (2021) stated that among their patients, they did not find a patient with 2 loss-of-function variants, 1 patient (patient 8) was homozygous for one of the variants (D1854N; 600286.0002) carried by the fetuses studied by Pagnamenta et al. (2015), which Verdura et al. (2021) stated carried 2 loss-of-function variants. Verdura et al. (2021) suggested that the fact that the D1854N variant in homozygosity led to a milder phenotype than that of the fetuses strongly suggests that this missense variant would not cause a complete loss of function, and that a certain degree of residual PI4KA activity was retained in patient 8. Additionally, patient 8 had polymicrogyria, as did the fetuses, suggesting that the D1854N variant may be specifically associated with that developmental brain abnormality.
In 6 unrelated patients (families 3-8) with NEDSPLB, Salter et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002; 600286.0011-600286.0014). The mutations were found by exome sequencing and segregated with the disorder in the families; the patients were ascertained through the GeneMatcher Program. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. In addition to developmental delay, spasticity, and leukoencephalopathy, some patients had inflammatory bowel disease and/or immunodeficiency.
Autosomal Recessive Spastic Paraplegia 84
In 2 unrelated patients (patients 9 and 10) with autosomal recessive spastic paraplegia-84 (SPG84; 619621), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene (600286.0006-600286.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed decreased PI4K protein levels compared to controls. Further studies showed that patients cells had decreased PI4KA activity compared to controls, consistent with the mutations being hypomorphic alleles. The authors postulated that the PIK4A gene and phosphoinositide signaling plays a role in myelination and brain development.
Gastrointestinal Defects And Immunodeficiency Syndrome 2
In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; 619708), Salter et al. (2021) identified a homozygous missense mutation in the PI4KA gene (Y1623D; 600286.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (609332), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; 243150). All patients with GIDI2 died of intestinal atresia in the first weeks of life; 2 patients had evidence of an immunodeficiency with lymphopenia.
In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with NEDSPLB (616531) manifest as perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA), Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene: a c.2386C-T transition (c.2386C-T, NM_058004.3) in exon 20, resulting in an arg796-to-ter (R796X) substitution, inherited from the unaffected father, and a c.5560G-A transition in exon 48, resulting in an asp1854-to-asn (D1854N; 600286.0002) substitution at a highly conserved residue in the kinase-binding domain, inherited from the unaffected mother. The mutations, which were found by a combination of exome sequencing and linkage analysis, were confirmed by Sanger sequencing. Neither mutation was found in 274 in-house genomes of mixed ancestry or in 500 Dutch genomes, but both were detected once in the ExAC database. Parental blood samples detected both mutations at the RNA level. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The fetuses were electively terminated between 16 and 34 weeks' gestation.
For discussion of the c.5560G-A transition (c.5560G-A, NM_058004.3) in the PI4KA gene, resulting in an asp1854-to-asn (D1854N) substitution, that was found in compound heterozygous state in tissue samples from 3 fetuses with perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA; see 616531) by Pagnamenta et al. (2015), see 600286.0001.
In a 5-year-old boy (patient 8), born of consanguineous Turkish parents, with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified a homozygous D1854N substitution in the PI4KA gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed. The patient had spastic tetraparesis, severe developmental delay, and polymicrogyria.
In a 13-year-old girl (P3), born of consanguineous Turkish parents, with NEDSPLB, Salter et al. (2021) identified a homozygous D1854N mutation in the PI4KA gene that segregated with the disorder in the family. Functional studies of the variant were not performed. The patient presented on the first day of life with refractory seizures and later showed severe global developmental delay, central hypotonia, peripheral spasticity, hypomyelinating leukodystrophy, immunodeficiency, and suspected inflammatory bowel disease.
In a 4-year-old girl (patient 1) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a 1-bp duplication (c.2624dupC) in exon 22, resulting in a frameshift and premature termination (Pro876SerfsTer36), and a c.3454G-A transition in exon 30, resulting in a glu1152-to-lys (E1152K; 600286.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.2624dupC mutation was found once in the gnomAD v2.1.1 database (1 of 250,576 alleles). The E1154K mutation was found once in the gnomAD v2.1.1 database (1 of 251,262 alleles). In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls.
For discussion of the c.3454G-A transition in the PI4KA gene, resulting in a glu1152-to-lys (E1152K; 600286.0004) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Verdura et al. (2021), see 600286.0003.
In a 19-year-old woman (patient 4) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a c.3592G-A transition in exon 31, resulting in an ala1198to-thr (A1198T) substitution at a conserved residue, and a 4-bp deletion in exon 53 (c.6156_6159delGACA; 600286.0006), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD v2.1.1 database. Western blot analysis of patient cells showed decreased protein levels compared to controls.
For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Verdura et al. (2021), see 600286.0003.
For discussion of the 4-bp deletion (c.6156_6159delGACA) in the PI4KA gene, resulting in a frameshift and premature termination (Thr2053SerfsTer4), that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; 619621), see 600286.0007.
In a 42-year-old man (patient 9) with autosomal recessive spastic paraplegia-84 (SPG84; 619621), Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a 3-bp deletion (c.5459_5461delAAG) in exon 47, resulting in an in-frame deletion of conserved residue (Glu1820del, E1820del), and a 4-bp deletion (c.6156_6159delGACA; 600286.0006), resulting in a frameshift and premature termination (Thr2053SerfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The Glu1820del mutation was not present in gnomAD v2.1.1, but was found in 1 of 143,164 alleles in v3. The c.6156_6159delGACA was not present in the gnomAD database. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls.
In an 18-year-old man of Hispanic descent (patient 10), with autosomal recessive spastic paraplegia-84 (SPG84; 619621) Verdura et al. (2021) identified compound heterozygous missense mutations in the PI4KA gene: a c.4666G-A transition in exon 39, resulting in a val1556-to-met (V1556M) substitution, and a c.5159C-T transition in exon 44, resulting in a thr1720-to-ile (T1720I; 600286.0009). Both mutations occurred at conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro studies indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls.
For discussion of the c.5159C-T transition in the PI4KA gene, resulting in a thr1720-to-ile (T1720I) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-84 (SPG84; 619621) by Verdura et al. (2021), see 600286.0008.
In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2; 619708), Salter et al. (2021) identified a homozygous c.4867T-G transversion (c.4867T-G, NM_058004.3) in the PI4KA gene, resulting in a tyr1623-to-asp (Y1623D) substitution at a conserved residue distal from the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the heterozygous state only in the gnomAD database (8.0 x 10(-6)). In vitro studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (609332), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; 243150). All infants died in the first weeks of life; 2 patients had evidence of an immunodeficiency.
In a 5-year-old girl (family 4) of Indian descent with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Salter et al. (2021) identified compound heterozygous mutations in the PI4KA gene: a c.5774G-A transition (c.5774G-A, NM_058004.3), resulting in a gly1925-to-glu (G1925E) substitution at a conserved residue in the catalytic domain, and a 1-bp deletion (c.6065delG; 600286.0012) in exon 52, predicted to result in a frameshift and premature termination (Arg2022GlnfsTer36). The mutations, which were found by trio-based whole-genome sequencing, segregated with the disorder in the family. Both were absent from the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. The patient had developmental delay, spasticity, leukoencephalopathy, colitis, and autoimmune enteropathy.
For discussion of the 1-bp deletion (c.6065delG, NM_058004.3) in exon 52 of the PI4KA gene, resulting in a frameshift and premature termination (Arg2022GlnfsTer36), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Salter et al. (2021), see 600286.0011.
In a 21-year-old German woman (family 7) with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531), Salter et al. (2021)m identified compound heterozygous mutations in the PI4KA gene: a c.2330T-C transition (c.2330T-C, NM_058004.3), resulting in a leu777-to-pro (L777P) substitution, and a c.3571C-T transition in exon 31, resulting in a gln1191-to-ter (Q1191X; 600286.0014) substitution. L777P was found at a low frequency in the heterozygous state in the gnomAD database (4 x 10(-6)), whereas Q1191X was not found in gnomAD. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but molecular modeling predicted that they would interfere with PI4KA function. The patient had global developmental delay, seizures, spasticity, and leukoencephalopathy. She did not have gastrointestinal disease or immunodeficiency.
For discussion of the c.3571C-T transition (c.3571C-T, NM_058004.3) in exon 31, resulting in a gln1191-to-ter (Q1191X) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB; 616531) by Salter et al. (2021), see 600286.0013.
Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., Messa, M., Baldassari, S., Assereto, S., Biancheri, R., Zara, F., Minetti, C., Raimondi, A., Simons, M., Walther, T. C., Reinisch, K. M., De Camilli, P. The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat. Cell Biol. 18: 132-138, 2016. [PubMed: 26571211] [Full Text: https://doi.org/10.1038/ncb3271]
Chung, J., Nakatsu, F., Baskin, J. M., De Camilli, P. Plasticity of PI4KIII-alpha interactions at the plasma membrane. EMBO Rep. 16: 312-320, 2015. [PubMed: 25608530] [Full Text: https://doi.org/10.15252/embr.201439151]
Gross, M. B. Personal Communication. Baltimore, Md. 1/29/2016.
Hammond, G. R. V., Fischer, M. J., Anderson, K. E., Holdich, J., Koteci, A., Balla, T., Irvine, R. F. PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science 337: 727-730, 2012. [PubMed: 22722250] [Full Text: https://doi.org/10.1126/science.1222483]
Nakagawa, T., Goto, K., Kondo, H. Cloning, expression, and localization of 230-kDa phosphatidylinositol 4-kinase. J. Biol. Chem. 271: 12088-12094, 1996. [PubMed: 8662589] [Full Text: https://doi.org/10.1074/jbc.271.20.12088]
Pagnamenta, A. T., Howard, M. F., Wisniewski, E., Popitsch, N., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Cox, H., Cox, P., Balla, T., Taylor, J. C., Kini, U. Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis. Hum. Molec. Genet. 24: 3732-3741, 2015. [PubMed: 25855803] [Full Text: https://doi.org/10.1093/hmg/ddv117]
Salter, C. G., Cai, Y., Lo, B., Helman, G., Taylor, H., McCartney, A., Leslie, J. S., Accogli, A., Zara, F., Traverso, M., Fasham, J., Lees, J. A., and 33 others. Biallelic PI4KA variants cause neurological, intestinal and immunological disease. Brain 144: 3597-3610, 2021. [PubMed: 34415310] [Full Text: https://doi.org/10.1093/brain/awab313]
Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. Brain 144: 2659-2669, 2021. [PubMed: 34415322] [Full Text: https://doi.org/10.1093/brain/awab124]
Wong, K., Cantley, L. C. Cloning and characterization of a human phosphatidylinositol 4-kinase. J. Biol. Chem. 269: 28878-28884, 1994. [PubMed: 7961848]