Alternative titles; symbols
HGNC Approved Gene Symbol: HPDL
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38): 1:45,326,895-45,328,710 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities | 619026 | Autosomal recessive | 3 |
| Spastic paraplegia 83, autosomal recessive | 619027 | Autosomal recessive | 3 |
HPDL is a mitochondrial protein that belongs to the vicinal oxygen chelate (VOC) superfamily of metalloenzymes (summary by Husain et al., 2020).
Husain et al. (2020) reported that the human HPDL protein contains 371 amino acids and shares sequence similarity with HPD (609695). It has a predicted N-terminal mitochondrial localization signal and 2 predicted VOC domains. HPDL is conserved across vertebrates. Database analysis suggested wide expression of human HPDL, with high levels in central and peripheral nervous systems. Immunohistologic analysis showed that human HPDL localized to mitochondria in transfected mouse Neuro2A cells.
Wiessner et al. (2021) showed that HPDL localized to the outer mitochondrial membrane in HeLa cells by both differential centrifugation and analysis of the mitochondrial fraction for the presence of HPDL as well as by cytochemical colocalization of HPDL with a mitochondrial immunofluorescence marker.
Husain et al. (2020) reported that the HPDL gene contains 1 exon.
Gross (2020) mapped the HPDL gene to chromosome 1p34.1 based on an alignment of the HPDL sequence (GenBank BC007293) with the genomic sequence (GRCh38).
Neurodevelopmental Disorder with Progressive Spasticity and Brain White Matter Abnormalities
In 12 patients from 9 unrelated families (families 1-9) with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Husain et al. (2020) identified homozygous or compound heterozygous mutations in the HPDL gene (see, e.g., 618994.0001-618994.0005). The mutations, which were found by exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. There were nonsense, frameshift, and missense mutations. Western blot analysis of fibroblasts derived from some of the patients showed significantly reduced HPDL protein levels compared to controls, suggesting that the mutations result in a loss-of-function effect. Additional functional studies of the variants were not performed. The patients were ascertained from several medical centers through international collaborative efforts and GeneMatcher.
In affected members of a consanguineous Pakistani kindred with NEDSWMA, previously reported by Mitchell and Bundey (1997) and McHale et al. (1999), Morgan et al. (2021) identified a homozygous missense mutation in the HPDL gene (L176P; 618994.0007). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both branches of the kindred. Functional studies of the variant and studies of patient cells were not performed. One branch of the family had previously been reported by Lynex et al. (2004) as having a homozygous missense variant in the GAD1 gene (S12C; 605363.0001), but the updated report by Morgan et al. (2021) noted that the GAD1 variant did not segregate in the family; the findings established that the HPDL mutation is actually the cause of the disorder in this family.
In 16 patients from 7 unrelated consanguineous families with NEDSWMA, Ghosh et al. (2021) identified homozygous or compound heterozygous mutations in the HPDL gene (see, e.g., 618994.0006, 618994.0010-618994.0013). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred in one of the VOC domains and were predicted to affect enzyme function. Functional studies of the variants and studies of patient cells were not performed, but knockdown of the HPDL gene in a cell line resulted in up- and downregulation of metabolites compared to controls, although tyrosine catabolism appeared to be unaffected. Additional studies of HPDL-null cells showed reduced oxygen consumption, suggesting an effect on mitochondrial metabolism. The authors concluded that the disorder is not only a mitochondrial neurodegenerative condition, but also likely a neurometabolic condition, and results from a loss of HPDL function.
Autosomal Recessive Spastic Paraplegia 83
In 3 unrelated patients (families 11-13) of Middle Eastern origin with autosomal recessive spastic paraplegia-83 (SPG83; 619027), Husain et al. (2020) identified a homozygous missense mutation in the HPDL gene (G50D; 618994.0006). An additional unrelated patient (family 10) with SPG83 was compound heterozygous for 2 mutations in the HPDL gene. The mutations, which were found by exome sequencing, segregated with the disorder in the families. Only the G50D mutation was found at a low frequency in the heterozygous state in the gnomAD database. Haplotype analysis of these families indicated a founder effect. Functional studies of the variants and studies of patient cells were not performed, but the authors hypothesized a loss-of-function effect.
In a girl, born of consanguineous Sudanese parents (family 2), with SPG83, Ghosh et al. (2021) identified a homozygous G50D mutation in the HPDL gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Mutations in HPDL Causing SPG3 or NEDSWMA
Wiessner et al. (2021) identified homozygous or compound heterozygous mutations in the HPDL gene in 34 individuals from 25 unrelated families with autosomal recessive SPG83 (10 patients) or NEDSWMA (24 patients). The mutations were identified by a combination of linkage analysis, whole-exome sequencing, whole-genome sequencing, and HPDL gene sequencing. Twenty-eight mutations were identified in the 25 families, 12 of which were consanguineous. The most common mutation identified was G50D (618994.0006), which was identified in 7 patients with SPG83 from 4 unrelated consanguineous families (families A, T, F and TUE). Protein levels and subcellular localization of HPDL with each of 10 missense mutations (see, e.g., G50D and I266T, 618994.0009) identified in this patient cohort were comparable to wildtype in transfected HeLa cells. However, Wiessner et al. (2021) tested the enzymatic function of these mutations at homologous sites in the related HPD gene (609695) in E. coli and found that enzymatic function was reduced. Wiessner et al. (2021) noted that truncating mutations in the HPDL tended to be more frequent in patients with severe disease compared to those with mild or intermediate disease, suggesting a correlation between residual enzymatic activity and phenotypic severity.
Ghosh et al. (2021) found that Hpdl-null mice developed seizures, had poor overall growth, and died before day 15 of life. Brains from mutant mice were smaller than those of controls and showed cellular apoptosis. There was no evidence of abnormalities in tyrosine catabolism.
In 2 sibs, born of unrelated Algerian parents (family 1), with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Husain et al. (2020) identified a homozygous 4-bp insertion (c.342_343insTGCC, NM_032756.3) in the HPDL gene, predicted to result in a frameshift and premature termination (Ala115CysfsTer82). The mutation, which was found by exome sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Since HPDL is a single-exon gene, the authors postulated that the mutant transcript would escape nonsense-mediated mRNA decay, resulting in a prematurely terminated protein and a loss of function. Western blot analysis of patient fibroblasts showed a significant decrease in HPDL protein levels compared to controls. Additional functional studies were not performed.
In 2 adult sibs, born of consanguineous Iranian parents (family 2), with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Husain et al. (2020) identified a homozygous c.779G-A transition (c.779G-A, NM_032756.3) in the HPDL gene, resulting in a gly260-to-glu (G260E) substitution at a conserved residue. The mutation, which was found by exome sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old boy, born of consanguineous Syrian parents (family 4) with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Husain et al. (2020) identified a homozygous c.1024C-T transition (c.1024C-T, NM_032756.3) in the HPDL gene, resulting in a gln342-to-ter (Q342X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Since HPDL is a single-exon gene, the authors postulated that the mutant transcript would escape nonsense-mediated mRNA decay, resulting in a prematurely terminated protein and a loss of function. Western blot analysis of patient fibroblasts showed a significant decrease in HPDL protein levels compared to controls. Additional functional studies were not performed.
In 2 brothers, born of unrelated German parents (family 6) with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Husain et al. (2020) identified compound heterozygous mutations in the HPDL gene: a c.503G-A transition (c.503G-A, NM_032756.3), resulting in a cys168-to-ter (C168X) substitution, and a c.537G-C transversion, resulting in a trp179-to-cys (W179C; 618944.0005) substitution at a conserved residue. The mutations, which were found by exome sequencing, segregated with the disorder in the family. Neither variant was present in the gnomAD database. Since HPDL is a single-exon gene, the authors postulated that the nonsense mutant transcript would escape nonsense-mediated mRNA decay, resulting in a prematurely terminated protein and a loss of function. Western blot analysis of patient fibroblasts showed a significant decrease in HPDL protein levels compared to controls. Additional functional studies were not performed.
For discussion of the c.537G-C transversion (c.537G-C, NM_032756.3) in the HPDL gene, resulting in a trp179-to-cys (W179C) substitution, that was found in compound heterozygous state in 2 brothers with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026) by Husain et al. (2020), see 618944.0004.
Autosomal Recessive Spastic Paraplegia 83
In 3 unrelated patients (families 11-13) of Middle Eastern origin with autosomal recessive spastic paraplegia-83 (SPG83; 619027), Husain et al. (2020) identified a homozygous c.149G-A transition (c.149G-A, NM_032756.3) in the HPDL gene, resulting in a gly50-to-asp (G50D) substitution at a highly conserved residue. The mutation, which was found by exome sequencing, segregated with the disorder in the families. It was found at a low frequency in the heterozygous state in the gnomAD database. Haplotype analysis of these families indicated a founder effect. Functional studies of the variants and studies of patient cells were not performed, but the authors hypothesized a loss-of-function effect.
In 7 patients from 4 unrelated consanguineous families with SPG83, including a sib pair from family A, a sib pair and a maternal uncle from family T, and single patients from families F and TUE, with SPG83, Wiessner et al. (2021) identified homozygosity for the G50D mutation in the HPDL gene. The mutations were identified by a combination of linkage analysis and whole-exome sequencing in family A, whole-exome sequencing in families F and T, and whole-genome sequencing in family TUE. All of the parents were shown to be mutation carriers. The mutation had an allele frequency of 1.018 x 10(-5) in the gnomAD database and was not present in the ESP and 1000 Genomes Project databases. Protein levels and subcellular localization of HPDL with the G50D mutation in transfected HeLa cells were comparable to wildtype; however, Wiessner et al. (2021) tested the enzymatic function of this mutation at a homologous site (G65D) in the related HPD gene (609695) in E. coli and found that enzymatic function was reduced.
In a girl, born of consanguineous Sudanese parents (family 2), with SPG83, Ghosh et al. (2021) identified a homozygous G50D mutation in the HPDL gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Neurodevelopmental Disorder with Progressive Spasticity and Brain White Matter Abnormalities
For discussion of the G50D mutation in the HPDL gene that was found in compound heterozygous state in 3 sibs with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026) identified by Ghosh et al. (2021), see 618994.0010.
In affected members of a consanguineous Pakistani kindred with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), previously reported by Mitchell and Bundey (1997) and McHale et al. (1999), Morgan et al. (2021) identified a homozygous c.527T-C transition in the HPDL gene, resulting in a leu176-to-pro (L176P) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both branches of the kindred. The variant was found only once in heterozygous state in the gnomAD database (1 of 244,766 alleles) in an individual of South Asian origin. Functional studies of the variant and studies of patient cells were not performed. One branch of the family had previously been reported by Lynex et al. (2004) as having a homozygous missense variant in the GAD1 gene (S12C; 605363.0001), but the updated report by Morgan et al. (2021) established that the HPDL mutation is actually the cause of the disorder in this family.
In 4 patients from unrelated consanguineous families, including 3 sibs from family E and 1 patient from family ZK, with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Wiessner et al. (2021) identified homozygosity for a 1-bp deletion (c.256del, NM_032756.3) in the N-terminal beta-barrel domain of the HPDL gene, predicted to result in a frameshift (Ala86fs). The mutations were identified by whole-exome sequencing. The mutation had an allele frequency of 4.896 x 10(-6) in the gnomAD database and not present in the ESP and 1000 Genomes Project databases. Functional studies were not performed.
In a patient (family D) with NEDSWMA, Wiessner et al. (2021) identified compound heterozygosity for 2 mutations in the HPDL gene: c.256del and a c.797C-T transition, resulting in an ile266-to-thr (I266T; 618994.0009) substitution in the C-terminal beta-barrel domain. The mutation was identified by whole-exome sequencing, and the parents were shown to be mutation carriers. The I266T mutation was reported with an allele frequency of 8.506 x 10(-6) in the gnomAD database and was not present in the ESP and 1000 Genomes Project databases. Protein levels and subcellular localization of HPDL with the I266T mutation in transfected HeLa cells were comparable to wildtype. However, Wiessner et al. (2021) tested the enzymatic function of this mutation at a homologous site (I274T) in the related HPD gene (609695) in E. coli and found that enzymatic function was reduced.
For discussion of the c.797C-T transition (c.797C-T, NM_032756.3) in the HPDL gene, resulting in an ile266-to-thr (I266T) substitution, that was identified in compound heterozygous state in a patient with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026) by Wiessner et al. (2021), see 618994.0008.
In 3 sibs, born of consanguineous Egyptian parents (family 1), with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Ghosh et al. (2021) identified compound heterozygous mutations in the HPDL gene: a 1-bp duplication (c.353dupA, NM_032756.2), resulting in a frameshift and premature termination (tyr118 to ter, Y118X), and a G50D substitution (618994.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were present at very low frequencies in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that both variants affected a VOC domain and likely resulted in loss of function of the enzyme.
In 3 sibs, born of consanguineous Egyptian parents (family 3) with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Ghosh et al. (2021) identified a homozygous c.232G-A transition (c.232G-A, NM_032756.2) in the HPDL gene, resulting in an ala78-to-thr (A78T) substitution at a conserved residue in the VOC domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in loss of function of the enzyme.
In 4 sibs, born of consanguineous Egyptian parents (family 6) with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Ghosh et al. (2021) identified a homozygous 1-bp duplication (c.954dup, NM_032756.2), resulting in a frameshift and premature termination (Gly319ArgfsTer15) in the second VOC domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In a boy, born of consanguineous Iranian parents (family 7), with neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026), Ghosh et al. (2021) identified a homozygous c.94C-T transition (c.94C-T, NM_032756.2) in the HPDL gene, resulting in a gln32-to-ter (Q32X) substitution in the first VOC domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
Ghosh, S. G., Lee, S., Fabunan, R., Chai, G., Zaki, M. S., Abdel-Salam, G., Sultan, T., Ben-Omran, T., Alvi, J. R., McEvoy-Venneri, J., Stanley, V., Patel, A., and 18 others. Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition. Genet. Med. 23: 524-533, 2021. [PubMed: 33188300] [Full Text: https://doi.org/10.1038/s41436-020-01010-y]
Gross, M. B. Personal Communication. Baltimore, Md. 8/20/2020.
Husain, R. A., Grimmel, M., Wagner, M., Hennings, J. C., Marx, C., Feichtinger, R. G., Saadi, A., Rostasy, K., Radelfahr, F., Bevot, A., Dobler-Neumann, M., Hartmann, H., and 34 others. Bi-allelic HPDL variants cause a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia. Am. J. Hum. Genet. 107: 364-373, 2020. [PubMed: 32707086] [Full Text: https://doi.org/10.1016/j.ajhg.2020.06.015]
Lynex, C. N., Carr, I. M., Leek, J. P., Achuthan, R., Mitchell, S., Maher, E. R., Woods, C. G., Bonthon, D. T., Markham, A. F. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with stiff-person syndrome and other movement disorders. BMC Neurol. 4: 20, 2004. Note: Electronic Article. [PubMed: 15571623] [Full Text: https://doi.org/10.1186/1471-2377-4-20]
McHale, D. P., Mitchell, S., Bundey, S., Moynihan, L., Campbell, D. A., Woods, C. G., Lench, N. J., Mueller, R. F., Markham, A. F. A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. Am. J. Hum. Genet. 64: 526-532, 1999. [PubMed: 9973289] [Full Text: https://doi.org/10.1086/302237]
Mitchell, S., Bundey, S. Symmetry of neurological signs in Pakistani patients with probable inherited spastic cerebral palsy. Clin. Genet. 51: 7-14, 1997. [PubMed: 9084927] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02406.x]
Morgan, N. V., Yngvadottir, B., O'Driscoll, M., Clark, G. R., Walsh, D., Martin, E., Tee, L., Reid, E., Titheradge, H. L., Maher, E. R. Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. Brain Commun. 3: fcab002, 2021. [PubMed: 33634263] [Full Text: https://doi.org/10.1093/braincomms/fcab002]
Wiessner, M., Maroofian R., Ni, M.-Y., Pedroni, A., Muller, J. S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F. M., Alfares, A. A., Zhu, C., Meszarosova, A. U., and 96 others. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain 144: 1422-1434, 2021. Note: Erratum: Brain 144: e70, 2021. [PubMed: 33970200] [Full Text: https://doi.org/10.1093/brain/awab041]