Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3

Ahmed, Saleem; Jelani, Musharraf; Alrayes, Nuha; Mohamoud, Hussein Sheikh Ali; Almramhi, Mona Mohammad; Anshasi, Wasim; Ahmed, Naushad; Wang, Jun; Nasir, Jamal; Al‐Aama, Jumana Y.

doi:10.1016/j.jns.2015.04.038

Cited by 38 publications

(48 citation statements)

References 19 publications

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“…Comparable symptoms have previously been reported in seven other families with CLPP defects (Table 2) (16, 21–24). Apart from the consistent involvement of SNHL, sex-related clinical features have been reported such as female ovarian dysgenesis and infertility due to azoospermia in males (15, 22).…”

Section: Discussionsupporting

confidence: 84%

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Theunissen

Szklarczyk

Gerards³

et al. 2016

Front. Neurol.

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In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient’s brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

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Section: Discussionsupporting

confidence: 84%

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Theunissen

Szklarczyk

Gerards³

et al. 2016

Front. Neurol.

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“…Since then, several familial and sporadic cases have been reported, of which, the majority was of European descent (2,5,8). PRLTS3 gene was identified in three Pakistani families (6) and we also screened a family from Saudi Arabia very recently (7). To date, only four mutations including one splicing (c.270+A>G) and three missense (c.433A>C; p.Thr145Pro, c.440G>C; p.Cys147Ser, c.685T>G; p.Tyr229Asp) have been identified in the CLPP gene (6,7).…”

Section: Discussionmentioning

confidence: 99%

“…PRLTS3 gene was identified in three Pakistani families (6) and we also screened a family from Saudi Arabia very recently (7). To date, only four mutations including one splicing (c.270+A>G) and three missense (c.433A>C; p.Thr145Pro, c.440G>C; p.Cys147Ser, c.685T>G; p.Tyr229Asp) have been identified in the CLPP gene (6,7). Here, we present, for the first time, a novel CLPP alteration in a Turkish family.…”

Section: Discussionmentioning

confidence: 99%

“…PRLTS type 2 is caused by mutations in HARS2 at chromosome 5q31.3 and is characterized by deafness in both males and females and gonadal dysgenesis in female patients only (5). PRLTS type 3 is caused by mutations in CLPP gene at chromosome 19p13.3 (6,7). PRLTS3 patients may present with progressive hearing loss, female infertility and premature menopause, microcephaly, epilepsy, growth and mental retardation (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…PRLTS type 3 is caused by mutations in CLPP gene at chromosome 19p13.3 (6,7). PRLTS3 patients may present with progressive hearing loss, female infertility and premature menopause, microcephaly, epilepsy, growth and mental retardation (6,7). PRLTS type 4 is caused by mutations in LARS2 gene at chromosome 3p21.31and is characterized by hearing loss and premature ovarian failure (8).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family

Dursun¹,

Mohamoud²,

Karim³

et al. 2016

Jcrpe

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Perrault syndrome (PRLTS) is a heterogeneous group of clinical and genetic disorders characterized by sensory neuronal hearing loss in both sexes and premature ovarian failure or infertility in females. Neurological and hearing loss symptoms appear early in life, but female infertility cannot be detected before puberty. Spastic limbs, muscle weakness, delayed puberty and irregular menstrual cycles have also been observed in PRLTS patients. Mutations in five genes, i.e. HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. Here, we report a milder phenotype of PRLTS in a Turkish family in which two affected patients had no neurological findings. However, both were characterized by sensory neuronal hearing loss and the female sibling had secondary amenorrhea and gonadal dysgenesis. Genome-wide homozygosity mapping using 300K single-nucleotide polymorphism microarray analysis together with iScan platform (Illumina, USA) followed by candidate gene Sanger sequencing with ABI 3500 Genetic Analyzer (Life Technologies, USA) were used for molecular diagnosis. We found a novel missense alteration c.624C>G; p.Ile208Met in exon 5 of the CLPP at chromosome 19p13.3. This study expands the mutation spectrum of CLPP pathogenicity in PRLTS type 3 phenotype.

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Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

et al. 2018

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Die caseinolytische Protease P( ClpP) ist die proteolytische Komponente des Protein-Abbau-Komplexes ClpXP.Ihre genaue Funktion und Regulation sind grçßtenteils unerforscht. Hier stellen wir eine niedermolekulare Verbindung (D9)v or,d ie durchN achahmung des natürlichen Chaperons ClpX als potenter und Spezies-selektiver Aktivator der humanen ClpP (hClpP) wirkt. Struktur-Aktivitäts-Studien hoben die Wichtigkeit eines halogenierten Benzyl-Motivs innerhalb von D9 hervor.D ieses interagiert mit einem einzigartigen aromatischen Aminosäure-Netzwerk in hClpP.M utations-und Strukturstudien legen nahe,d ass dieses sogenannte YYW-Motiv die hClpP-Aktivitäts treng kontrolliert und den Substratumsatz durchI nteraktion mit passenden Liganden reguliert. Ferner ist dieses Motiv besonders fürC lpP hçherer Organismen charakteristischu nd existiert nichti ng etesteten bakteriellen Homologen. Dies erlaubt eine Spezies-selektive Analyse,womit D9 ein vielseitiges Werkzeug fürdie Untersuchung von mechanistischen Eigenschaften der hClpP werden kann.

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Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3

Cited by 38 publications

References 19 publications

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family

Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

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