title: Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.
abstract: Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPR(mt)) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.
authors.affiliation: Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Jenkinson
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Drummond
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Muhammad Asif
authors.initials: MA
authors.lastname: Naeem
authors.forename: Bushra
authors.initials: B
authors.lastname: Rauf
authors.forename: Neil
authors.initials: N
authors.lastname: Billington
authors.forename: Julie M
authors.initials: JM
authors.lastname: Schultz
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Berry
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: Sarju
authors.initials: S
authors.lastname: Mehta
authors.forename: Deirdre
authors.initials: D
authors.lastname: Cilliers
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Warner
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.forename: Dorothy
authors.initials: D
authors.lastname: Trump
authors.forename: Julian R E
authors.initials: JR
authors.lastname: Davis
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D049071:Endopeptidase Clp / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D023961:Gonadal Dysgenesis, 46,XX / Q000209:etiology*; D006319:Hearing Loss, Sensorineural / Q000209:etiology*; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D000255:Adenosine Triphosphate; D049069:ATP-Dependent Proteases; C568646:ClpP protein, human; D049071:Endopeptidase Clp
references.citation: Nat Struct Biol. 2001 Mar;8(3):230-3
references.pmid: 11224567
references.citation: J Biol Chem. 1993 Oct 25;268(30):22609-17
references.pmid: 8226769
references.citation: Biochemistry. 1995 Aug 29;34(34):10910-7
references.pmid: 7662672
references.citation: Hear Res. 2011 Nov;281(1-2):3-10
references.pmid: 21664957
references.citation: Bull Mem Soc Med Hop Paris. 1951 Jan 26-Feb 2;67(3-4):79-84
references.pmid: 14821788
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6543-8
references.pmid: 21464306
references.citation: Am J Med Genet A. 2004 Jul 30;128A(3):246-9
references.pmid: 15216544
references.citation: FEBS Lett. 2007 Jul 31;581(19):3749-57
references.pmid: 17499722
references.citation: J Biol Chem. 2010 May 7;285(19):14834-40
references.pmid: 20236930
references.citation: Cell. 1997 Nov 14;91(4):447-56
references.pmid: 9390554
references.citation: Cerebellum. 2012 Dec;11(4):982-1001
references.pmid: 22528962
references.citation: Genome Biol. 2008;9 Suppl 1:S4
references.pmid: 18613948
references.citation: J Mol Biol. 2008 Jun 13;379(4):760-71
references.pmid: 18468623
references.citation: Cell. 1998 Jun 12;93(6):973-83
references.pmid: 9635427
references.citation: Genome Res. 2009 Sep;19(9):1527-41
references.pmid: 19546169
references.citation: Am J Hum Genet. 2010 Jun 11;86(6):963-9
references.pmid: 20560210
references.citation: Am J Med Genet. 1994 May 15;51(1):81-2
references.pmid: 8030674
references.citation: J Neurol. 2012 May;259(5):974-6
references.pmid: 22037954
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):282-8
references.pmid: 20673864
references.citation: Mol Cell Biol. 2007 Jan;27(2):758-67
references.pmid: 17101804
references.citation: Mol Cells. 2011 Dec;32(6):589-95
references.pmid: 22080375
references.citation: J Biol Chem. 2012 Mar 16;287(12):9484-94
references.pmid: 22291011
references.citation: Acta Crystallogr D Biol Crystallogr. 2007 Feb;63(Pt 2):249-59
references.pmid: 17242518
references.citation: Hum Genet. 2011 Dec;130(6):759-65
references.pmid: 21660509
references.citation: Cell Signal. 2006 Aug;18(8):1226-34
references.pmid: 16298104
references.citation: PLoS Genet. 2011 Oct;7(10):e1002325
references.pmid: 22022284
references.citation: Amyotroph Lateral Scler. 2011 Mar;12(2):148-9
references.pmid: 21190509
references.citation: J Struct Biol. 2006 Oct;156(1):165-74
references.pmid: 16682229
references.citation: Hear Res. 1994 Jan;72(1-2):44-52
references.pmid: 8150744
references.citation: J Struct Biol. 2004 Dec;148(3):338-52
references.pmid: 15522782
references.citation: Neuroscience. 2008 May 2;153(2):474-82
references.pmid: 18378094
references.citation: Genet Med. 1999 Jul-Aug;1(5):207-12
references.pmid: 11256674
references.citation: Am J Med Genet. 1996 Nov 11;65(4):274-6
references.pmid: 8923934
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):90-4
references.pmid: 20602914
references.citation: Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9999-10003
references.pmid: 1946469
references.citation: FEBS Lett. 1995 Dec 18;377(2):249-52
references.pmid: 8543061
references.citation: J Struct Biol. 2006 Feb;153(2):113-28
references.pmid: 16406682
references.citation: Nat Struct Mol Biol. 2010 Apr;17(4):471-8
references.pmid: 20305655
references.citation: Hum Mutat. 2006 Oct;27(10):1041-6
references.pmid: 16941472
references.citation: Nat Genet. 2010 Sep;42(9):790-3
references.pmid: 20711175
references.citation: Brain Res Mol Brain Res. 2002 Sep 30;105(1-2):1-10
references.pmid: 12399102
references.citation: Chem Biol. 2010 Sep 24;17(9):959-69
references.pmid: 20851345
references.citation: Mol Cell Neurosci. 2009 Jan;40(1):62-75
references.pmid: 18930827
references.citation: Hum Reprod. 2000 Jul;15 Suppl 2:129-47
references.pmid: 11041520