Alternative titles; symbols
HGNC Approved Gene Symbol: HSPA9
SNOMEDCT: 1260203008;
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38) : 5:138,553,756-138,575,401 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.2 | Anemia, sideroblastic, 4 | 182170 | Autosomal dominant | 3 |
| Even-plus syndrome | 616854 | Autosomal recessive | 3 |
HSPA9 is a highly conserved member of the HSP70 family of proteins (see 140550). It functions as a chaperone in the mitochondria, cytoplasm, and centrosome (summary by Chen et al., 2011).
Mortalin has been shown to exhibit differential distributions in cells with mortal and immortal phenotypes. All immortal human and mouse cells that have been tested are devoid of the uniformly distributed cytosolic form of the protein that is characteristic of normal cells. Kaul et al. (1995) cloned mortalin cDNA from an immortal cell line, RS-4, established from mouse fibroblasts. The cDNA exhibited the structure of the perinuclear form, Mot2.
Using FISH, Kaul et al. (1995) mapped the human mortalin gene to chromosome 5q31.1. Gross (2011) mapped the HSPA9 gene to chromosome 5q31.2 based on an alignment of the HSPA9 sequence (GenBank AK222758) with the genomic sequence.
In mouse, Kaul et al. (1995) mapped mortalin-related genes to chromosomes 18 and X.
By immunoprecipitation analysis of mitochondria from human lymphoblasts and transfected COS-7 cells, Shan et al. (2007) showed that frataxin (FXN; 606829), which is encoded by the gene mutated in Friedreich ataxia (FRDA; 229300), interacted directly with several mitochondrial proteins, including the mitochondrial chaperone HSPA9. Reciprocal immunoprecipitation analysis confirmed the interaction of FXN and HSPA9 in transfected HEK293 cells.
Using various binding assays, Dong et al. (2019) showed that Grp75 bound directly to frataxin, preferentially to the frataxin precursor, in mouse brain cortex and neuronal cells. Grp75 also interacted with Mpp (613036) and potentiated interaction of Mpp with frataxin, which facilitated frataxin maturation. Frataxin deficiency in FRDA cells correlated with GRP75 reduction, but frataxin overexpression or knockdown had no effect on GRP75 expression in HEK293 cells and human skin fibroblasts. These findings suggested that GRP75 reduction in FRDA patient cells was due to a chronic, secondary effect of frataxin deficiency rather than a direct effect. GRP75 overexpression increased proteins levels of wildtype frataxin and frataxin mutants in HEK293 cells, whereas GRP75 loss-of-function mutants reduced expression of frataxin and binding of GRP75 to frataxin. Both mitochondria-targeted GRP75 and cytosolic GRP75 overexpression increased frataxin and rescued ATP deficit in FRDA patient cells. However, only mitochondria-targeted GRP75 expression rescued abnormalities of mitochondrial morphology in FRDA patient cells.
Heterozygous deletions spanning chromosome 5q31.2 occur frequently in myelodysplastic syndromes (153550). Chen et al. (2011) purified human cord blood hematopoietic progenitor cells and grew them under culture conditions that supported erythroid, myeloid, or megakaryocytic cell growth. They found that short hairpin RNA-mediated knockdown of HSPA9 in these progenitors reduced growth predominantly in erythroid progenitors. Knockdown of HSPA9 in erythroid cultures was associated with an increased number of cells in the G0/G1 phase of the cell cycle and accelerated apoptosis. Knockdown of Hspa9 in mouse bone marrow cells, followed by transplantation into wildtype recipients, also resulted in loss of erythroid cell number. Chen et al. (2011) concluded that haploinsufficiency for HSPA9 may contribute to abnormal hematopoiesis in myelodysplastic syndromes with deletions spanning chromosome 5q31.2.
Sideroblastic Anemia 4
In a 4-generation Dutch kindred with mild congenital sideroblastic anemia mapping to chromosome 5q (SIDBA4; 182170), Schmitz-Abe et al. (2015) analyzed the candidate gene HSPA9 and identified a heterozygous 2-bp deletion (600548.0001) that segregated with the disease. Affected individuals from a second family with sideroblastic anemia mapping to 5q were heterozygous for an in-frame 6-bp deletion in HSPA9 (600548.0002). Sequencing of 88 other probands with congenital sideroblastic anemia revealed 9 additional patients with at least 1 HSPA9 variant with a frequency of less than 1% in the Exome Variant Server database. Schmitz-Abe et al. (2015) noted that some families with HSPA9 variants appeared to demonstrate autosomal recessive inheritance, and observed that the minor T allele of the synonymous SNP rs10117, which correlated with reduced mRNA expression, was present in trans in 9 of 10 affected individuals from the first 2 families. Phenotype permutation analysis of 21 individuals heterozygous for a presumptive HSPA9 coding mutation yielded a p value less than 0.07, suggesting that the rs10117 T allele or a linked variant determines expression of the HSPA9 sideroblastic anemia phenotype in patients with a single unambiguously deleterious allele. Schmitz-Abe et al. (2015) concluded that this form of sideroblastic anemia is an autosomal recessive disorder, with a pseudodominant pattern of inheritance in some families.
EVEN-Plus Syndrome
In 2 Chilean sisters and a Korean girl with EVEN-plus syndrome (616854), Royer-Bertrand et al. (2015) identified mutations in the HSPA9 gene: the 2 sisters were homozygous for a missense mutation (R126W; 600548.0003), whereas the Korean girl was compound heterozygous for a missense (Y128C; 600548.0004) and a nonsense mutation (V296X; 600548.0005).
Possible Association with Parkinson Disease
Because mortalin expression was found by Jin et al. (2007) to be decreased in pathologically verified Parkinson disease (PD; see 168600), De Mena et al. (2009) screened the 17 coding exons of HSPA9 in 330 Spanish PD patients and 250 ethnically matched controls and identified different heterozygous variants in 3 patients with late-onset disease. The mutations, including a splice site variant (IVS11-16C-T) and 2 missense variants (c.376G-A, R126W; c.1526G-A, P509S), were not found in controls. No functional studies were performed.
By screening the coding region of the mortalin gene in a sample of 286 German PD patients, Burbulla et al. (2010) identified another missense variant (A476T; 600548.0006) in 1 patient, which was not found in 580 control chromosomes. Screening of an independent cohort of 1,008 German PD patients and 1,342 controls for the A476T variant and the 2 missense variants reported by De Mena et al. (2009) identified the A476T in 4 additional PD patients (mean age at onset in carriers, 53 +/- 11 years). The A476T variant was also found in 6 controls; 4 reportedly had extrapyramidal symptoms that did not fulfill the diagnostic criteria for PD and 2 had a mean age of 44.5 +/- 9.5 years. The other missense variants were not found in patients or controls. In neuronal and nonneuronal human cell lines, all 3 disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments corresponded to characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wildtype, which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss-of-function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wildtype mortalin, but not by the variants. Burbulla et al. (2010) concluded that a loss of mortalin function causes impaired mitochondrial function and dynamics, and they proposed a role for aberrant mortalin in neurodegeneration.
Chung et al. (2017) investigated the role of HSPA9 and its interaction with other mitochondria-related genes as a risk factor for Parkinson disease and Alzheimer disease (AD; see 104300) in 500 PD, 400 AD, and 500 control subjects. HSPA9 variants, including the 3 studied by Burbulla et al. (2010), did not show a significant association with PD or AD risk.
By sequencing the coding region of mortalin in 139 patients with early-onset PD, Freimann et al. (2013) identified a heterozygous missense variant (c.1073T-C, L358P) that was absent in 279 controls. They also found a missense variant (c.998C-A, T333K) in the control group. Neither variant was present in the NHLBI Exome Sequencing Project database, and both variants were predicted to be pathogenic by software analysis. However, in SH-SY5Y cell lines, stably expressing wildtype or mutant mortalin with either variant, mortalin colocalized with mitochondria, and the morphology of the mitochondrial network was intact under basal conditions. The mitochondrial network even remained unaffected after metabolic stress induced by growth in galactose media. No differences were observed in mitochondrial respiration between mutant and wildtype mortalin.
In a 4-generation Dutch kindred with mild congenital sideroblastic anemia mapping to chromosome 5q (SIDBA4; 182170), originally described by van Waveren Hogervorst et al. (1987), Schmitz-Abe et al. (2015) identified heterozygosity for a 2-bp deletion (c.409_410del, NM_004134.6) in the HSPA9 gene, causing a frameshift resulting in a premature termination codon (I137X). Of 7 affected individuals, 6 also carried the minor T allele of the synonymous SNP rs10117 (c.1933T) in trans. Analysis of individuals homozygous for the T allele showed that they expressed approximately 50% of HSPA9 mRNA and 80% of HSPA9 protein, compared to individuals homozygous for the C allele. However, there was substantial overlap in the level of expression in the homozygous groups, with some C allele homozygotes having as little mRNA or protein expression as the majority of T homozygotes. Schmitz-Abe et al. (2015) suggested that rs10117 T or a linked variant determines expression of the HSPA9 SDBA phenotype in patients with a single unambiguously deleterious allele, but that the T allele itself is not deterministic.
In a father, daughter, and son with sideroblastic anemia mapping to chromosome 5q (SIDBA4; 182170), Schmitz-Abe et al. (2015) identified heterozygosity for a 6-bp deletion (c.1373_1378del, NM_004134.6) in the HSPA9 gene, resulting in an in-frame deletion of 2 amino acids (I458_N459del). All 3 affected individuals also carried the minor T allele of the synonymous SNP rs10117 (c.1933T) in trans. Analysis of individuals homozygous for the T allele showed that they expressed approximately 50% of HSPA9 mRNA and 80% of HSPA9 protein, compared to individuals homozygous for the C allele. However, there was substantial overlap in the level of expression in the homozygous groups, with some C allele homozygotes having as little mRNA or protein expression as the majority of T homozygotes. Schmitz-Abe et al. (2015) suggested that rs10117 T or a linked variant determines expression of the HSPA9 sideroblastic anemia phenotype in patients with a single unambiguously deleterious allele, but that the T allele itself is not deterministic.
In 2 Chilean sisters with EVEN-plus syndrome (EVPLS; 616854), Royer-Bertrand et al. (2015) identified homozygosity for a c.376C-T transition in the HSPA9 gene, resulting in an arg126-to-trp (R126W) substitution at a highly conserved residue within the nucleotide-binding domain. Their parents were heterozygous for the mutation, which was found at extremely low frequency in the ExAC database (0.00002471) and was absent from the Exome Variant Server database.
In a Korean girl with EVEN-plus syndrome (EVPLS; 616854), Royer-Bertrand et al. (2015) identified compound heterozygosity for a c.383A-G transition in the HSPA9 gene, resulting in a tyr128-to-cys (Y128C) substitution at a highly conserved residue within the nucleotide-binding domain, and a 2-bp deletion (c.882_883delAG) causing a frameshift resulting in a premature termination codon (V296X; 600548.0005), predicted to abolish more than half the protein. Her parents were each heterozygous for 1 the mutations, which were found at extremely low frequency in the ExAC database (0.000008236 and 0.0001977, respectively) and were absent from the Exome Variant Server database.
For discussion of the 2-bp deletion (c.882_883delAG) in the HSPA9 gene, causing a frameshift resulting in a premature termination codon (V296X), that was found in compound heterozygous state in a Korean girl with EVEN-plus syndrome (EVPLS; 616854) by Royer-Bertrand et al. (2015), see 600548.0004.
This variant is classified as a variant of unknown significance because its contribution to Parkinson disease (see 168600) has not been confirmed.
In 2 German cohorts totaling 1,294 Parkinson disease (PD) patients, Burbulla et al. (2010) identified 5 patients who were heterozygous for a c.1426G-A transition in the HSPA9 gene, resulting in an ala476-to-thr (A476T) substitution in a highly conserved region of the protein that forms part of the substrate-binding domain. The variant was also found in 6 of 1,632 control individuals, 4 of whom reportedly had extrapyramidal symptoms that did not fulfill the diagnosis of PD. In vitro import assays revealed normal targeting of the variant. In neuronal and nonneuronal human cell lines, the variant caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which was exacerbated upon proteolytic stress. These functional impairments corresponded with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wildtype, which was confirmed in fibroblasts from a carrier of the A476T variant. Knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wildtype mortalin, but not by the variant.
Chung et al. (2017) investigated the role of HSPA9 and its interaction with other mitochondria-related genes as a risk factor for Parkinson disease and Alzheimer disease (AD) in 500 PD, 400 AD, and 500 control subjects. HSPA9 variants, including A476T, did not show a significant association with PD or AD risk.
Hamosh (2017) noted that the A476T variant in the HSPA9 gene was present in 40 of 121,372 alleles (allele frequency of 0.0003296) in the ExAC database (July 11, 2017).
Burbulla, L. F., Schelling, C., Kato, H., Rapaport, D., Woitalla, D., Schiesling, C., Schulte, C., Sharma, M., Illig, T., Bauer, P., Jung, S., Nordheim, A., Schols, L., Riess, O., Kruger, R. Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis. Hum. Molec. Genet. 19: 4437-4452, 2010. [PubMed: 20817635] [Full Text: https://doi.org/10.1093/hmg/ddq370]
Chen, T. H.-P., Kambal, A., Krysiak, K., Walshauser, M. A., Raju, G., Tibbitts, J. F., Walter, M. J. Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. Blood 117: 1530-1539, 2011. [PubMed: 21123823] [Full Text: https://doi.org/10.1182/blood-2010-06-293167]
Chung, S. J., Kim, M.-J., Ryu, H.-S., Kim, J., Kim, Y. J., Kim, K., You, S., Kim, S. Y., Lee, J.-H. Lack of association of mortalin (HSPA9) and other mitochondria-related genes with risk of Parkinson's and Alzheimer's diseases. Neurobiol. Aging 49: 215.e9-215.e10, 2017. Note: Electronic Article. [PubMed: 28340952] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2016.09.017]
De Mena, L., Coto, E., Sanchez-Ferrero, E., Ribacoba, R., Guisasola, L. M., Salvador, C., Blazquez, M., Alvarez, V. Mutational screening of the mortalin gene (HSPA9) in Parkinson's disease. J. Neural Transm. 116: 1289-1293, 2009. [PubMed: 19657588] [Full Text: https://doi.org/10.1007/s00702-009-0273-2]
Dong, Y. N., McMillan, E., Clark, E. M., Lin, H., Lynch, D. R. GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich ataxia cellular models. Hum. Molec. Genet. 28: 1594-1607, 2019. [PubMed: 30590615] [Full Text: https://doi.org/10.1093/hmg/ddy448]
Freimann, K., Zschiedrich, K., Bruggemann, N., Grunewald, A., Pawlack, H., Hagenah, J., Lohmann, K., Klein, C., Westenberger, A. Mortalin mutations are not a frequent cause of early-onset Parkinson disease. Neurobiol. Aging 34: 2694.e19-2694.e20, 2013. [PubMed: 23831374] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2013.05.021]
Gross, M. B. Personal Communication. Baltimore, Md. 9/12/2011.
Hamosh, A. Personal Communication. Baltimore, Md. July 11, 2017.
Jin, J., Li, G. J., Davis, J., Zhu, D., Wang, Y., Pan, C., Zhang, J. Identification of novel proteins associated with both alpha-synuclein and DJ-1. Molec. Cell Proteomics 6: 845-859, 2007. [PubMed: 16854843] [Full Text: https://doi.org/10.1074/mcp.M600182-MCP200]
Kaul, S. C., Wadhwa, R., Matsuda, Y., Hensler, P. J., Pereira-Smith, O. M., Komatsu, Y., Mitsui, Y. Mouse and human chromosomal assignments of mortalin, a novel member of the murine hsp70 family of proteins. FEBS Lett. 361: 269-272, 1995. [PubMed: 7698336] [Full Text: https://doi.org/10.1016/0014-5793(95)00177-b]
Royer-Bertrand, B., Castillo-Taucher, S., Moreno-Salinas, R., Cho, T.-J., Chae, J.-H., Choi, M., Kim, O.-H., Dikoglu, E., Campos-Xavier, B., Girardi, E., Superti-Furga, G., Bonafe, L., Rivolta, C., Unger, S., Superti-Furga, A. Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia. Sci. Rep. 5: 17154, 2015. Note: Electronic Article. [PubMed: 26598328] [Full Text: https://doi.org/10.1038/srep17154]
Schmitz-Abe, K., Ciesielski, S. J., Schmidt, P. J., Campagna, D. R., Rahimov, F., Schilke, B. A., Cuijpers, M., Rieneck, K., Lausen, B., Linenberger, M. L., Sendamarai, A. K., Guo, C., and 16 others. Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. Blood 126: 2734-2738, 2015. [PubMed: 26491070] [Full Text: https://doi.org/10.1182/blood-2015-09-659854]
Shan, Y., Napoli, E., Cortopassi, G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum. Molec. Genet. 16: 929-941, 2007. [PubMed: 17331979] [Full Text: https://doi.org/10.1093/hmg/ddm038]
van Waveren Hogervorst, G. D., van Roermund, H. P. C., Snijders, P. J. Hereditary sideroblastic anaemia and autosomal inheritance of erythrocyte dimorphism in a Dutch family. Europ. J. Haemat. 38: 405-409, 1987. [PubMed: 3653362] [Full Text: https://doi.org/10.1111/j.1600-0609.1987.tb01436.x]