Alternative titles; symbols
HGNC Approved Gene Symbol: CLPP
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,361,531-6,370,242 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Perrault syndrome 3 | 614129 | Autosomal recessive | 3 |
CLPP (EC 3.4.21.92), a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response stress signaling pathway (summary by Jenkinson et al., 2013).
ATP-dependent proteases were first identified in E. coli. Bross et al. (1995) stated that one of these, called ClpAP or Ti, consists of a regulatory unit, ClpA, with chaperone characteristics and an ATPase domain, and a proteolytic subunit, ClpP. This protease is involved in ATP-dependent degradation of abnormal (i.e., incorrectly folded or unfolded) proteins. Bross et al. (1995) identified 3 overlapping human ESTs with significant homology to the E. coli ClpP amino acid sequence. With this sequence information, they applied RACE to amplify and sequence human CLPP cDNA. The open reading frame encodes a 277-amino acid precursor polypeptide. Northern blot analysis showed high relative expression levels of CLPP mRNA in skeletal muscle, intermediate levels in heart, liver, and pancreas, and low levels in brain, placenta, lung, and kidney.
By analysis of human/rodent cell hybrids, Bross et al. (1995) mapped the human CLPP gene to chromosome 19.
Santagata et al. (1999) reported that the CLPP gene maps to chromosome 19q13.
By electron microscopy, Kang et al. (2002) determined that purified recombinant human CLPP and CLPX (615611) formed heptameric and hexameric rings, respectively. The holoenzyme CLPXP contained 2 heptameric rings of CLPP bound on each side by a hexameric ring of CLPX. CLPXP was stable in the presence of ATP or a nonhydrolyzable ATP analog. In the absence of CLPX, CLPP showed proteolytic activity against protein substrates and a 10-residue E. coli ClpP substrate. Activity was enhanced in the presence of CLPX. E. coli or mouse Clpx interacted with human CLPP in functional complexes that had different substrate specificities than E. coli ClpXP holoenzymes. Mutation analysis revealed ser97 as the catalytic residue of CLPP.
Kang et al. (2005) found that isolated human CLPP was a stable heptamer with an apparent molecular mass of 169.2 kD. The heptamer had no proteolytic activity and very low peptidase activity. In the presence of ATP, human CLPX interacted with CLPP, forming a complex with an apparent molecular mass of over 1 million Da. The CLPXP holoenzyme had protease activity and greatly increased peptidase activity, suggesting that interaction with CLPX affects the conformation of the CLPP catalytic active site.
In affected individuals from 3 unrelated consanguineous Pakistani families with Perrault syndrome mapping to chromosome 19p13 (PRLTS3; 614129), Jenkinson et al. (2013) identified homozygosity for 2 missense mutations and 1 splice site mutation in the CLPP gene (601119.0001-601119.0003).
In 2 affected sibs from a Turkish family with Perrault syndrome mapping to chromosome 19p13, Dursun et al. (2016) identified homozygosity for a missense mutation in the CLPP gene (I208M; 601119.0004) that segregated with disease and was not found in controls or in public variant databases.
Gispert et al. (2013) obtained Clpp -/- mice in less than the expected mendelian ratio. Surviving Clpp -/- pups were similar in weight to wildtype littermates until weaning, but thereafter they showed slower weight gain and were smaller than wildtype as adults. Adult Clpp -/- mice of both sexes were completely infertile, showed reduced spontaneous motor activity, developed deafness, and died from natural causes earlier than wildtype. However, Clpp -/- mice were resistant to ulcerative dermatitis, which normally affects 5% of all mice with C57BL/6 background. Histologically, infertility in Clpp -/- males was accompanied by absence of spermatids and mature spermatozoa in testis. Infertility in Clpp -/- females was accompanied by reduced ratio of corpora lutea versus follicles before rupture. The number of mitochondrial complexes in Clpp -/- heart and liver were reduced compared with wildtype, but they were normal in Clpp -/- brain. Absence of Clpp was associated with elevated content of Clpx protein and other mitochondrial matrix chaperones, tissue-dependent dysregulation of nuclear-encoded genes, elevated mitochondrial DNA but measurable respiratory deficit, and strong activation of splenic T cells. Gispert et al. (2013) hypothesized that the phenotype of Clpp -/- mice is consistent with deficient clearance of mitochondrial components and inflammatory tissue destruction.
In 3 affected sisters with Perrault syndrome (PRLTS3; 614129) from a consanguineous British Pakistani family (PDF1) originally reported by Jenkinson et al. (2012), Jenkinson et al. (2013) identified homozygosity for a c.433A-C transversion in exon 4 of the CLPP gene, resulting in a thr145-to-pro (T145P) substitution at a highly conserved residue (chr19:6,364,528; GRCh37) within the beta-3 strand of the first beta sheet in the head region. The mutation segregated with disease in the family and was not found in 193 ethnically matched controls or in the NHLBI Exome Variant Server (ESP6500). In addition to profound congenital sensorineural hearing loss and premature ovarian failure, the sisters exhibited short stature, microcephaly, seizures, moderate learning difficulties, and truncal and cerebellar ataxia with signs of lower limb spasticity.
In 4 affected sisters with Perrault syndrome (PRLTS3; 614129) from a consanguineous Pakistani family (PKDF291) previously reported by Ain et al. (2007) and Rehman et al. (2011) as having DFNB81, Jenkinson et al. (2013) identified homozygosity for a c.440G-C transversion in exon 4 of the CLPP gene, resulting in a cys147-to-ser (C147S) substitution at a highly conserved residue (chr19:6,364,535; GRCh37) within the beta-3 strand of the first beta sheet in the head region. The mutation segregated with disease in the family and was not found in 483 ethnically matched controls or in the NHLBI Exome Variant Server (ESP6500). In addition to hearing loss, the 4 affected sisters had primary amenorrhea and hypogonadism.
In a brother and 2 sisters with features of Perrault syndrome (PRLTS3; 614129) from a consanguineous Pakistani family (DEM4395), Jenkinson et al. (2013) identified homozygosity for a c.270+4A-G transition in intron 2 of the CLPP gene (chr19:6,361,955; GRCh37), predicted to abolish the splice donor site of exon 2. Splicing assays in COS-7 cells suggested that the c.270+4A-G mutant allele does not fully ablate donor splice site function but rather weakens it. The variant was not found in 386 ethnically matched controls. The 3 affected sibs had profound congenital sensorineural hearing loss, but no additional self-reported medical problems; formal evaluation of hormone profiles was not possible.
In a Turkish sister and brother with Perrault syndrome (PRLTS3; 614129), Dursun et al. (2016) identified homozygosity for a c.624C-G transversion in exon 5 of the CLPP gene, resulting in an ile208-to-met (I208M) substitution. Their unaffected parents were both heterozygous for the mutation, which was not found in 100 controls or in the 1000 Genomes Project or ExAC databases.
Ain, Q., Nazli, S., Riazuddin, S., Jaleel, A., Riazuddin, S. A., Zafar, A. U., Khan, S. N., Husnain, T., Griffith, A. J., Ahmed, Z. M., Friedman, T. B., Riazuddin, S. The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3. Hum. Genet. 122: 445-450, 2007. [PubMed: 17690910] [Full Text: https://doi.org/10.1007/s00439-007-0418-z]
Bross, P., Andresen, B. S., Knudsen, I., Kruse, T. A., Gregersen, N. Human ClpP protease: cDNA sequence, tissue-specific expression and chromosomal assignment of the gene. FEBS Lett. 377: 249-252, 1995. [PubMed: 8543061] [Full Text: https://doi.org/10.1016/0014-5793(95)01353-9]
Dursun, F., Mohamoud, H. S. A., Karim, N., Naeem, M., Jelani, M., Kirmizibekmez, H. A novel missense mutation in the CLPP gene causing Perrault syndrome type 3 in a Turkish family. J. Clin. Res. Pediat. Endocr. 8: 472-477, 2016. [PubMed: 27087618] [Full Text: https://doi.org/10.4274/jcrpe.2717]
Gispert, S., Parganlija, D., Klinkenberg, M., Drose, S., Wittig, I., Mittelbronn, M., Grzmil, P., Koob, S., Hamann, A., Walter, M., Buchel, F., Adler, T., de Angelis, M. H., Busch, D. H., Zell, A., Reichert, A. S., Brandt, U., Osiewacz, H. D., Jendrach, M., Auburger, G. Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Hum. Molec. Genet. 22: 4871-4887, 2013. [PubMed: 23851121] [Full Text: https://doi.org/10.1093/hmg/ddt338]
Jenkinson, E. M., Clayton-Smith, J., Mehta, S., Bennett, C., Reardon, W., Green, A., Pearce, S. H. S., De Michele, G., Conway, G. S., Cilliers, D., Moreton, N., Davis, J. R. E., Trump, D., Newman, W. G. Perrault syndrome: further evidence for genetic heterogeneity. J. Neurol. 259: 974-976, 2012. [PubMed: 22037954] [Full Text: https://doi.org/10.1007/s00415-011-6285-5]
Jenkinson, E. M., Rehman, A. U., Walsh, T., Clayton-Smith, J., Lee, K., Morell, R. J., Drummond, M. C., Khan, S. N., Asif Naeem, M., Rauf, B., Billington, N., Schultz, J. M., and 20 others. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am. J. Hum. Genet. 92: 605-613, 2013. [PubMed: 23541340] [Full Text: https://doi.org/10.1016/j.ajhg.2013.02.013]
Kang, S. G., Dimitrova, M. N., Ortega, J., Ginsburg, A., Maurizi, M. R. Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. J. Biol. Chem. 280: 35424-35432, 2005. [PubMed: 16115876] [Full Text: https://doi.org/10.1074/jbc.M507240200]
Kang, S. G., Ortega, J., Singh, S. K., Wang, N., Huang, N., Steven, A. C., Maurizi, M. R. Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP. J. Biol. Chem. 277: 21095-21102, 2002. [PubMed: 11923310] [Full Text: https://doi.org/10.1074/jbc.M201642200]
Rehman, A. U., Gul, K., Morell, R. J., Lee, K., Ahmed, Z. M., Riazuddin, S., Ali, R. A., Shahzad, M., Jaleel, A., Andrade, P. B., Khan, S. N., Khan, S., Brewer, C. C., Ahmad, W., Leal, S. M., Riazuddin, S., Friedman, T. B. Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Hum. Genet. 130: 759-765, 2011. [PubMed: 21660509] [Full Text: https://doi.org/10.1007/s00439-011-1018-5]
Santagata, S., Bhattacharyya, D., Wang, F.-H., Singha, N., Hodtsev, A., Spanopoulou, E. Molecular cloning and characterization of a mouse homolog of bacterial ClpX, a novel mammalian class II member of the Hsp100/Clp chaperone family. J. Biol. Chem. 274: 16311-16319, 1999. [PubMed: 10347188] [Full Text: https://doi.org/10.1074/jbc.274.23.16311]