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caseinolytic mitochondrial matrix peptidase proteolytic subunit OKDB#: 5074
 Symbols: CLPP Species: human
 Synonyms: DFNB81, PRLTS3  Locus: 19p13.3 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment NCBI Summary: The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]
General function
Comment
Cellular localization Mitochondrial
Comment
Ovarian function
Comment Metabolic imaging with the use of fluorescence lifetime imaging microscopy (FLIM) accurately detects mitochondrial dysfunction in mouse oocytes. Sanchez T et al. (2018) To determine whether metabolic imaging with the use of fluorescence lifetime imaging microscopy (FLIM) identifies metabolic differences between normal oocytes and those with metabolic dysfunction. Experimental study. Academic research laboratories. None. Oocytes from mice with global knockout of Clpp (caseinolytic peptidase P; n = 52) were compared with wild-type (WT) oocytes (n = 55) as a model of severe oocyte dysfunction. Oocytes from old mice (1 year old; n = 29) were compared with oocytes from young mice (12 weeks old; n = 35) as a model of mild oocyte dysfunction. FLIM was used to measure the naturally occurring nicotinamide adenine dinucleotide dehydrogenase (NADH) and flavin adenine dinucleotide (FAD) autofluorescence in individual oocytes. Eight metabolic parameters were obtained from each measurement (4 per fluorophore): short (τ1) and long (τ2) fluorescence lifetime, fluorescence intensity (I), and fraction of the molecule engaged with enzyme (F). Reactive oxygen species (ROS) levels and blastocyst development rates were measured to assess illumination safety. In Clpp-knockout oocytes compared with WT, FAD τ1 and τ2 were longer and I was higher, NADH τ2 was longer, and F was lower. In old oocytes compared with young ones, FAD τ1 was longer and I was lower, NADH τ1 and τ2 were shorter, and I and F were lower. FLIM did not affect ROS levels or blastocyst development rates. FLIM parameters exhibit strong differentiation between Clpp-knockout versus WT, and old versus young oocytes. FLIM could potentially be used as a noninvasive tool to assess mitochondrial function in oocytes.//////////////////
Expression regulated by
Comment
Ovarian localization Oocyte
Comment
Follicle stages
Comment
Phenotypes POF (premature ovarian failure)
Mutations 4 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Perrault Syndrome Pagon RA 1993 et al. DISEASE CHARACTERISTICS Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females, and ovarian dysfunction in females. The SNHL is bilateral and ranges in severity from moderate with early-childhood onset to profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some affected women include developmental delay or intellectual disability, cerebellar ataxia, and motor and sensory peripheral neuropathy. DIAGNOSIS/TESTING The diagnosis of Perrault syndrome is based on the clinical findings of SNHL in men and women, and ovarian dysfunction in women with a 46,XX karyotype. The diagnosis is confirmed by the presence of biallelic pathogenic variants in one of four genes (HARS2, HSD17B4, LARS2, or CLPP); to date, however, biallelic pathogenic variants in one of these four genes have been identified in individuals in seven families only. MANAGEMENT Treatment of manifestations: Hearing loss should be assessed and treated by a multidisciplinary team including an audiologist and otolaryngologist. Possible interventions for those with hearing loss include special educational resources, hearing aids, vibrotactile devices, and cochlear implantation. Cochlear implantation is an option for children older than 12 months with severe-to-profound hearing loss. Primary amenorrhea is treated in adolescents in collaboration with a pediatric endocrinologist in the usual manner first to induce puberty and then to mimic the menstrual cycle and maintain bone health. Assisted reproduction through in vitro fertilization using donor eggs is a consideration for women with gonadal dysgenesis; oocyte cryopreservation can be considered in women at risk for primary ovarian insufficiency. Prevention of secondary complications: In consultation with a reproductive endocrinologist, estrogen replacement treatment should be combined with progesterone to reduce the risk for endometrial cancer. Surveillance: For women with primary amenorrhea: during induction of puberty, follow up every three months for staging of pubertal development and adjustment of estrogen dose. For women on maintenance estrogen replacement therapy: annual follow up as well as approximately every five-year assessment of bone density. Routine audiologic assessments when hearing loss is mild to moderate; no follow up or audiologic assessments when hearing loss is profound. For children with hearing impairment: monitor development Agents/circumstances to avoid: Avoid: ototoxic medication (e.g., aminoglycosides) if alternatives are available; exposure to loud noise, which can exacerbate hearing loss. Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures (e.g., early intervention in young children with profound hearing loss). GENETIC COUNSELING Perrault syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk require prior molecular identification of the pathogenic variants causing Perrault syndrome in the family. /////////////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Gispert S et al. (2013) The caseinolytic peptidase P (CLPP) is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of CLPP null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre-implantation embryos. Wang T et al. (2019) Caseinolytic peptidase P mediates degradation of unfolded mitochondrial proteins and activates mitochondrial unfolded protein response (mtUPR) to maintain protein homeostasis. Clpp-/- female mice generate a lower number of mature oocytes and two-cell embryos, and no blastocysts. Clpp-/- oocytes have smaller mitochondria, with lower aspect ratio (length/width), and decreased expression of genes that promote fusion. A 4-fold increase in atretic follicles at 3 months, and reduced number of primordial follicles at 6-12 months are observed in Clpp-/- ovaries. This is associated with upregulation of p-S6, p-S6K, p-4EBP1 and p-AKT473, p-mTOR2481 consistent with mTORC1 and mTORC2 activation, respectively, and Clpp-/- oocyte competence is partially rescued by mTOR inhibitor rapamycin. Our findings demonstrate that CLPP is required for oocyte and embryo development and oocyte mitochondrial function and dynamics. Absence of CLPP results in mTOR pathway activation, and accelerated depletion of ovarian follicular reserve.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Mitochondrial Stress Response Gene Clpp Is Not Required for Granulosa Cell Function. Esencan E et al. (2020) Mitochondrial unfolded protein response (UPRmt) is a highly conserved mechanism, which is activated upon cellular or metabolic stress and aims to help cells maintain homeostasis. CLPP (caseinolytic peptidase P) plays a crucial factor for UPRmt; it promotes the degradation of unfolded mitochondrial proteins. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Here, we asked whether CLPP is necessary for granulosa/cumulus cell function. Clppflox/flox mice were generated and crossbred with Cyp19a1-Cre mice to generate mice with granulosa/cumulus cell-specific Clpp deletion (Clpp-/-). Mature (8-week-old) Clpp-/- female mice (8-week-old) were compared to same age wild type (WT) mice. We found that mature Clpp-/- female mice were fertile and produced a similar number of pups per litter compared to WT. Folliculogenesis was not affected by the loss of CLPP in granulosa/cumulus cells as Clpp-/- and WT mice had a similar number of primordial, primary, secondary, early antral, and antral follicles. The number of germinal vesicles (GV) and MII oocytes collected from Clpp-/- and WT female mice were also similar. Our findings demonstrate that fertility in female mice is not affected by granulosa/cumulus cell-specific UPRmt disruption through CLPP deletion.//////////////////

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created: Sept. 26, 2014, 4:06 p.m. by: hsueh   email:
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last update: Jan. 8, 2021, 12:07 a.m. by: hsueh    email:



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