HGNC Approved Gene Symbol: PANK2
SNOMEDCT: 2992000; ICD10CM: G23.0;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:3,888,781-3,929,887 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | Neurodegeneration with brain iron accumulation 1 | 234200 | Autosomal recessive | 3 |
Pantothenate kinase (EC 2.7.2.33) is an essential regulatory enzyme in CoA biosynthesis, catalyzing the cytosolic phosphorylation of pantothenate (vitamin B5), N-pantothenoylcysteine, and pantetheine. CoA is the major acyl carrier, playing a central role in intermediary and fatty acid metabolism. In both yeast and fly, each with only 1 pantothenate kinase gene, the null mutant is inviable (summary by Zhou et al., 2001).
Using linkage analysis of an extended Amish pedigree, Taylor et al. (1996) defined an interval on 20p13 that contains the gene mutant in Hallervorden-Spatz disease, now known as neurodegeneration with brain iron accumulation-1 (NBIA1; 234200). Zhou et al. (2001) narrowed the critical region for the disorder by genotyping polymorphic microsatellite markers in affected families. Analysis of candidate genes in this 1.4-Mb region led to the identification in the index family of a 7-bp deletion in the coding sequence of a gene with homology to murine pantothenate kinase-1. PANK2 is a member of a family of eukaryotic genes consisting of a group of 6 exons that encode homologous core proteins, preceded by a series of alternate initiating exons, some of which encode unique N-terminal peptides. By 5-prime RACE and EST analysis, Zhou et al. (2001) found evidence for at least 5 initiating exons for PANK2, but only 1 of these, exon 1C, has an open reading frame with potential initiation codons that splices in-frame to exon 2. Zhou et al. (2001) found a sequence similar to that of human PANK2 in mouse, with homology in the derived amino acid sequence extending to the leucine codon at nucleotide 31 but diverging 5-prime of it. There is precedence for the use of a leucine initiating codon in humans, which is probably read by a methionine tRNA. The leucine codon is flanked by a reasonable initiation consensus sequence. Zhou et al. (2001) also noted the presence of a stem-loop structure 14 nucleotides downstream from this leucine, the location of which has been shown to enhance translation initiation at nonconserved AUG and non-AUG initiation codons. The mouse stem-loop sequence is nearly identical, with only 3 nucleotide changes, 2 in the postulated loop of the stem loop and 1 that changes a GC to a GU basepair, which implies structural conservation. Because of this strong conservation, Zhou et al. (2001) proposed that the CUG may serve as an alternative initiation codon for translation in addition to one of the methionine codons downstream. There is also a 22-bp palindrome at the junction of spliced exons 1C and 2. This sequence may form a hairpin structure and thus explain why most PANK2 ESTs terminate just 3-prime of the palindrome. Zhou et al. (2001) speculated that this sequence may serve a regulatory function. PANK2 is ubiquitously expressed, including in retina and infant basal ganglia. Zhou et al. (2001) provided evidence for pantothenic kinase activity in PANK2 by showing that the human gene PANK2 can rescue the temperature-sensitive E. coli pantothenate kinase mutant.
Hortnagel et al. (2003) determined the exon-intron structure of the human PANK2 gene and identified 2 alternatively used first exons. The resulting transcripts encode distinct isoforms of PANK2, one of which carries an N-terminal extension with a predicted mitochondrial targeting signal. An in vitro import assay and in vivo immunolocalization experiments demonstrated a mitochondrial localization of this isoform. The authors concluded that the symptoms observed in pantothenate kinase-associated neurodegeneration (234200) may be caused by a deficiency of the mitochondrial isoform; they further postulated the existence of a complete intramitochondrial pathway for de novo synthesis of coenzyme A.
Zhou et al. (2001) identified 3 nonsense mutations in exon 1C of the PANK2 gene in affected individuals with classic Hallervorden-Spatz disease, also known as neurodegeneration with brain iron accumulation-1 (NBIA1; 234200) or pantothenate kinase-associated neurodegeneration (PKAN), but not in controls.
Hayflick et al. (2003) performed clinical assessment and mutation screen of the PANK2 gene on 123 patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome, classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). PANK2 mutations were found in 66 of the 98 families. Of 49 families whose members had classic disease, all had mutations in PANK2. Of 49 families whose members had atypical disease, mutations were found in 17 (35%). Whereas almost all mutations in patients with atypical disease were missense, those in patients with classic disease resulted more often in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted MRI of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations. Predicted levels of pantothenate kinase-2 protein correlated with the severity of the disease.
In the 66 families with mutations in the PANK2 gene studied by Hayflick et al. (2003), 2 PANK2 mutations, both of them missense mutations, accounted for one-third of the disease alleles, G411R (606157.0002) and T418M (606157.0010). G411R constituted 31 disease-related alleles in 27 families. Eighty-one percent of the 27 families with the G411R mutation were of European descent. In 6 families (4 with classic disease and 2 with atypical disease), the G411R mutation was found on one chromosome and no mutation was identified on the other. Families with only 1 identified mutation were not distinguishable from those with 2. Some of these mutations were undetectable with the screening method used, e.g., promoter mutations. Six of the 9 families with a single mutant allele had only the allele with the G411R mutation. This observation is striking because mutations in both alleles were detected in nearly all families, and it suggests that G411R may be semidominant, with 1 allele sufficient to cause disease given certain genetic backgrounds. Against this hypothesis was the fact that no disease phenotype was observed in G411R-heterozygous carrier parents of affected persons.
In 16 patients with PKAN, Pellecchia et al. (2005) identified 12 mutations in the PANK2 gene, including 5 novel mutations. They found no genotype/phenotype correlations.
Hartig et al. (2006) identified homozygous or compound heterozygous PANK2 mutations in 48 of 72 patients with PKAN. Deletions accounted for 4% of mutated alleles. There was a correlation between predicted loss-of-function alleles and earlier age at disease onset.
In a patient with NBIA1, who was originally reported as having 'HARP syndrome' by Higgins et al. (1992), Ching et al. (2002) identified a homozygous nonsense mutation in the PANK2 gene (R371X; 606157.0011). The patient had classic features of PKAN, but also had a specific lipoprotein abnormality.
In 20 patients from the Dominican Republic with NBIA1, Delgado et al. (2012) identified a homozygous missense mutation in the PANK2 gene (Y227C; 606157.0016). One homozygous carrier was asymptomatic at 7 years of age ('preclinical' case). Functional studies of the variant were not performed.
Kuo et al. (2005) generated a mouse knockout of the murine Pank2 gene. Homozygous null mice gradually developed retinal degeneration with progressive photoreceptor decline, significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment, and reduced pupillary constriction response. Homozygous male mutants were infertile due to azoospermia, a condition that was not appreciated in affected humans with pantothenate kinase-associated neurodegeneration (234200). In contrast to the human, homozygous null mice exhibited no basal ganglia changes or dystonia. By immunohistochemistry, Pank2 was localized to mitochondria in both retina and spermatozoa.
Drosophila has only 1 PANK gene, fumble (fbl), which encodes several isoforms of pantothenate kinase, including a long isoform fblL that localizes to mitochondria and shorter isoforms fblS1 and fblS2 that localize to the cytosol. Wu et al. (2009) introduced various isoforms of Drosophila fbl and human PANK2 into flies to study their in vivo functions. Only mitochondria-targeted FblL or human PANK2 was able to rescue a hypomorphic fbl(1) mutation, with the rescuing ability dependent on the expression level of the transgene. Transgenic lines with low expression of normal fbl or PANK2 displayed similar phenotypes as PANK2-mutant transgenic flies. These PANK2 mutants all showed reduced enzyme activity, and phenotype severity correlated with in vitro enzyme activity. Cytosolic PANK3 (606161) and PANK4 (606162) could partially rescue all fbl defects except male sterility. The authors concluded that fbl is the ortholog of human PANK2, and PANK2 is functionally more potent than PANK3 and PANK4 in vivo. Wu et al. (2009) suggested that mitochondria-located pantothenate kinase is required to achieve the maximal enzymatic activity to fulfill the most challenging biologic tasks such as maintaining male fertility and optimal neuronal function, and PKAN features are mainly due to the reduction of the total cellular pantothenate kinase activity in the most susceptible regions.
In an individual with classic pantothenate kinase-associated neurodegeneration (234200), Zhou et al. (2001) identified a homozygous 7-bp deletion in exon 2 of the PANK2 gene, resulting in a frameshift.
In 10 individuals with classic pantothenate kinase-associated neurodegeneration (234200), Zhou et al. (2001) identified a homozygous 1261G-A transition in exon 6 of the PANK2 gene, resulting in a glycine-to-arginine substitution at codon 411 (G411R). The mutation was also seen in 7 individuals with atypical PKAN.
In an individual with classic pantothenate kinase-associated neurodegeneration (234200), Zhou et al. (2001) identified a C-to-G transversion at nucleotide 270 in exon 1C of the PANK2 gene, resulting in a tyrosine-to-termination substitution at codon 80 (Y80X). This mutation was found in compound heterozygosity with arg154 to tyr (606157.0004). In another affected individual, the mutation was found in homozygosity.
In an individual with classic pantothenate kinase-associated neurodegeneration (234200), Zhou et al. (2001) found a C-to-T transition at nucleotide 490 of the PANK2 gene, resulting in an arg-to-trp substitution at codon 154 (R154W). This patient was compound heterozygous for the Y80X mutation (606157.0003).
In an individual with classic pantothenate kinase-associated neurodegeneration (234200), Zhou et al. (2001) identified a C-to-T transition at nucleotide 556 of the PANK2 gene, resulting in an arg-to-cys substitution at codon 176 (R176C). This individual was a compound heterozygote for the G411R mutation (606157.0002).
In an individual with classic pantothenate kinase-associated neurodegeneration (234200) who was compound heterozygous for an R145W mutation (606157.0004) in the PANK2 gene, Zhou et al. (2001) identified a G-to-A transition on the other allele, resulting in a ser361-to-asn (S361N) amino acid substitution.
In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified a homozygous mutation, a T-to-C transition at nucleotide 751 of the PANK2 gene, resulting in a serine-to-proline substitution at codon 240 (S240P).
In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified an A-to-G transition at nucleotide 400 of the PANK2 gene, resulting in a threonine-to-alanine substitution at codon 124 (T124A).
In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified a C-to-T transition at nucleotide 532of the PANK2 gene, resulting in an arg-to-cys substitution at codon 168 (R168C). This patient was compound heterozygous for the G411R mutation (606157.0002).
In individuals with both typical and atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified a C-to-T transition at nucleotide 1283 of the PANK2 gene, resulting in a threonine-to-methionine substitution at codon 418 (T418M). This mutation was found in homozygosity in 2 patients with classical PKAN, and in compound heterozygosity with the G411R mutation (606157.0002) in an individual with atypical PKAN.
Hayflick et al. (2003) found the T418M mutation on 10 alleles in 6 of 66 families with PANK2 mutations causing Hallervorden-Spatz syndrome.
In a patient with neurodegeneration with brain iron accumulation-1 (NBIA1; 234200), Ching et al. (2002) demonstrated homozygosity for a C-to-T transition at nucleotide 1111 in exon 5 of the PANK2 gene. The mutation changed an arginine codon to a stop codon at amino acid 371 and shortened PANK2 by 89 amino acids. Ching et al. (2002) suspected that the patient was the offspring of consanguineous parents because they came from a village of 500 inhabitants. The patient demonstrated severe spasticity and dystonia from early childhood. At age 10, she was shown to have pigmentary retinopathy on funduscopic examination and the 'eye of the tiger' sign on brain MRI. Peripheral blood smear and electron microscopy demonstrated marked acanthocytosis that was not due to an intrinsic erythrocyte protein defect. On high-resolution lipoprotein electrophoresis, she demonstrated absence of the pre-beta fraction and normal blood levels of cholesterol, triglycerides, high and low density lipoprotein cholesterol, and apolipoproteins A, B, and E. The patient was originally reported by Higgins et al. (1992) as having 'HARP syndrome' due to a lipoprotein abnormality.
In a patient with neurodegeneration with brain iron accumulation-1 (NBIA1; 234200), Houlden et al. (2003) identified compound heterozygosity for mutations in the PANK2 gene: a 980T-C change in exon 4, resulting in a met327-to-thr (M327T) substitution, and a splice site mutation (606157.0013). Her unaffected father and 2 of his unaffected brothers were heterozygous for the M327T mutation. The patient's mother and sister, both of whom had acanthocytosis and hypoprebetalipoproteinemia without neurologic abnormalities, were heterozygous for the splice site mutation. The proband was initially reported by Orrell et al. (1995) as having 'HARP syndrome' due to a lipoprotein abnormality.
For discussion of the G-to-T transversion at the splice site of exon 5 (IVS4-1G-T) in the PANK2 gene that was found in compound heterozygous state in a patient with neurodegeneration with brain iron accumulation-1 (NBIA1; 234200) by Houlden et al. (2003), see 606157.0012.
Hayflick et al. (2003) identified the IVS4-1G-T mutation in 2 patients with NBIA1.
In affected members from 4 Dutch families with pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Rump et al. (2005) identified a 3-bp deletion (1142delGAG) in the PANK2 gene. The in-frame deletion is predicted to result in substitution of arg371 and glu372 with a glutamine in the catalytic domain of the protein. Five patients from 3 families were homozygous for the mutation. The patient from the fourth family was compound heterozygous for the deletion and a second mutation (S68X; 606157.0015). Haplotype analysis suggested a founder effect that arose in Friesland, a northern province of the Netherlands, at the beginning of the ninth century, approximately 38 generations ago.
In a Dutch patient with pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Rump et al. (2005) identified compound heterozygosity for 2 mutations in the PANK2 gene: a 3-bp deletion (606157.0014) and a 233C-A transversion, resulting in a ser68-to-ter (S68X) substitution. The patient had a severe form of the disorder and died at age 12 years.
In 20 patients from the Dominican Republic with neurodegeneration with brain iron accumulation-1 (NBIA1; 234200), Delgado et al. (2012) identified a homozygous c.680A-G transition in the PANK2 gene, resulting in a tyr227-to-cys (Y227C) substitution. One homozygous carrier was asymptomatic at 7 years of age ('preclinical' case). Functional studies of the variant were not performed.
Schiessl-Weyer et al. (2015) examined erythrocyte morphology in 25 patients from the Dominican Republic with PKAN and a homozygous Y227C mutation (c.680A-G, NM_153638.2) in exon 2 of the PANK2 gene, most of whom were previously reported by Delgado et al. (2012). Schiessl-Weyer et al. (2015) noted that PANK2 and other enzymes of the coenzyme A biosynthetic pathway are normal constituents of the erythrocyte cytosol; they hypothesized that reduced CoA levels could result in aberrant lipid-based signaling processes and dysfunctional organization of protein complexes at the erythrocyte plasma membrane. The somewhat later onset of disease in these patients (average 10.8 years), absence of pigmentary retinopathy, and mild or no intellectual decline suggested that the mutant protein likely has some residual enzymatic activity.
Ching, K. H. L., Westaway, S. K., Gitschier, J., Higgins, J. J., Hayflick, S. J. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 58: 1673-1674, 2002. [PubMed: 12058097] [Full Text: https://doi.org/10.1212/wnl.58.11.1673]
Delgado, R. F., Sanchez, P. R., Speckter, H., Then, E. P., Jimenez, R., Oviedo, J., Dellani, P. R., Foerster, B., Stoeter, P. Missense PANK2 mutation without 'eye of the tiger' sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN). J Magn. Reson. Imaging 35: 788-794, 2012. [PubMed: 22127788] [Full Text: https://doi.org/10.1002/jmri.22884]
Hartig, M. B., Hortnagel, K., Garavaglia, B., Zorzi, G., Kmiec, T., Klopstock, T., Rostasy, K., Svetel, M., Kostic, V. S., Schuelke, M., Botz, E., Weindl, A., Novakovic, I., Nardocci, N., Prokisch, H., Meitinger, T. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann. Neurol. 59: 248-256, 2006. [PubMed: 16437574] [Full Text: https://doi.org/10.1002/ana.20771]
Hayflick, S. J., Westaway, S. K., Levinson, B., Zhou, B., Johnson, M. A., Ching, K. H. L., Gitschier, J. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. New Eng. J. Med. 348: 33-40, 2003. [PubMed: 12510040] [Full Text: https://doi.org/10.1056/NEJMoa020817]
Higgins, J. J., Patterson, M. C., Papadopoulos, N. M., Brady, R. O., Pentchev, P. G., Barton, N. W. Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 42: 194-198, 1992. [PubMed: 1734303] [Full Text: https://doi.org/10.1212/wnl.42.1.194]
Hortnagel, K., Prokisch, H., Meitinger, T. An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria. Hum. Molec. Genet. 12: 321-327, 2003. [PubMed: 12554685] [Full Text: https://doi.org/10.1093/hmg/ddg026]
Houlden, H., Lincoln, S., Farrer, M., Cleland, P. G., Hardy, J., Orrell, R. W. Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic. Neurology 61: 1423-1426, 2003. [PubMed: 14638969] [Full Text: https://doi.org/10.1212/01.wnl.0000094120.09977.92]
Kuo, Y.-M., Duncan, J. L., Westaway, S. K., Yang, H., Nune, G., Xu, E. Y., Hayflick, S. J., Gitschier, J. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum. Molec. Genet. 14: 49-57, 2005. [PubMed: 15525657] [Full Text: https://doi.org/10.1093/hmg/ddi005]
Orrell, R. W., Amrolia, P. J., Heald, A., Cleland, P. G., Owen, J. S., Morgan-Hughes, J. A., Harding, A. E., Marsden, C. D. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology 45: 487-492, 1995. [PubMed: 7898702] [Full Text: https://doi.org/10.1212/wnl.45.3.487]
Pellecchia, M. T., Valente, E. M., Cif, L., Salvi, S., Albanese, A., Scarano, V., Bonuccelli, U., Bentivoglio, A. R., D'Amico, A., Marelli, C., Di Giorgio, A., Coubes, P., Barone, P., Dallapiccola, B. The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 64: 1810-1812, 2005. [PubMed: 15911822] [Full Text: https://doi.org/10.1212/01.WNL.0000161843.52641.EC]
Rump, P., Lemmink, H. H., Verschuuren-Bemelmans, C. C., Grootscholten, P. M., Fock, J. M., Hayflick, S. J., Westaway, S. K., Vos, Y. J., van Essen, A. J. A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect. Neurogenetics 6: 201-207, 2005. [PubMed: 16240131] [Full Text: https://doi.org/10.1007/s10048-005-0018-9]
Schiessl-Weyer, J., Roa, P., Laccone, F., Kluge, B., Tichy, A., De Almeida Ribeiro, E., Prohaska, R., Stoeter, P., Siegl, C., Salzer, U. Acanthocytosis and the c.680 A-G mutation in the PANK2 gene: a study enrolling a cohort of PKAN patients from the Dominican Republic. PLoS One 10: e0125861, 2015. [PubMed: 25915509] [Full Text: https://doi.org/10.1371/journal.pone.0125861]
Taylor, T. D., Litt, M., Kramer, P., Pandolfo, M., Angelini, L., Nardocci, N., Davis, S., Pineda, M., Hattori, H., Flett, P. J., Cilio, M. R., Bertini, E., Hayflick, S. J. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nature Genet. 14: 479-481, 1996. Note: Erratum: Nature Genet. 16: 109 only, 1997. [PubMed: 8944032] [Full Text: https://doi.org/10.1038/ng1296-479]
Wu, Z., Li, C., Lv, S., Zhou, B. Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model. Hum. Molec. Genet. 18: 3659-3672, 2009. [PubMed: 19602483] [Full Text: https://doi.org/10.1093/hmg/ddp314]
Zhou, B., Westaway, S. K., Levinson, B., Johnson, M. A., Gitschier, J., Hayflick, S. J. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nature Genet. 28: 345-349, 2001. [PubMed: 11479594] [Full Text: https://doi.org/10.1038/ng572]