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

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          Abstract

          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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          Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

          An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole‐exome sequencing (WES), are identifying the genetic basis of disease for 25–40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation‐wide effort to identify mutations for childhood‐onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
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            The structure of ClpP at 2.3 A resolution suggests a model for ATP-dependent proteolysis.

            We have determined the crystal structure of the proteolytic component of the caseinolytic Clp protease (ClpP) from E. coli at 2.3 A resolution using an ab initio phasing procedure that exploits the internal 14-fold symmetry of the oligomer. The structure of a ClpP monomer has a distinct fold that defines a fifth structural family of serine proteases but a conserved catalytic apparatus. The active protease resembles a hollow, solid-walled cylinder composed of two 7-fold symmetric rings stacked back-to-back. Its 14 proteolytic active sites are located within a central, roughly spherical chamber approximately 51 A in diameter. Access to the proteolytic chamber is controlled by two axial pores, each having a minimum diameter of approximately 10 A. From the structural features of ClpP, we suggest a model for its action in degrading proteins.
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              Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome.

              Perrault syndrome is a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations. No genes for Perrault syndrome have heretofore been identified. A small family of mixed European ancestry includes two sisters with well-characterized Perrault syndrome. Whole-exome sequencing of genomic DNA from one of these sisters revealed exactly one gene with two rare functional variants: HSD17B4, which encodes 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4), also known as D-bifunctional protein (DBP). HSD17B4/DBP is a multifunctional peroxisomal enzyme involved in fatty acid beta-oxidation and steroid metabolism. Both sisters are compound heterozygotes for HSD17B4 c.650A>G (p.Y217C) (maternal allele) and HSB17B4 c.1704T>A (p.Y568X) (paternal allele). The missense mutation is predicted by structural analysis to destabilize the HSD17B4 dehydrogenase domain. The nonsense mutation leads to very low levels of HSD17B4 transcript. Expression of mutant HSD17B4 protein in a compound heterozygote was severely reduced. Mutations in HSD17B4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid beta-oxidation that is generally fatal within the first two years of life. No females with DBP deficiency surviving past puberty have been reported, and ovarian dysgenesis has not previously been associated with this illness. Six other families with Perrault syndrome have wild-type sequences of HSD17B4. These results indicate that Perrault syndrome and DBP deficiency overlap clinically; that Perrault syndrome is genetically heterogeneous; that DBP deficiency may be underdiagnosed; and that whole-exome sequencing can reveal critical genes in small, nonconsanguineous families.
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                Author and article information

                Journal
                J Clin Res Pediatr Endocrinol
                J Clin Res Pediatr Endocrinol
                JCRPE
                Journal of Clinical Research in Pediatric Endocrinology
                Galenos Publishing
                1308-5727
                1308-5735
                December 2016
                1 December 2016
                : 8
                : 4
                : 472-477
                Affiliations
                [1 ] Ümraniye Training and Research Hospital, Clinic of Pediatric Endocrinology, İstanbul, Turkey
                [2 ] King Abdulaziz University, Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia
                [3 ] St. George’s University of London, Human Genetics Research Centre, Division of Biomedical Sciences, London, United Kingdom
                [4 ] Quaid-I-Azam University Faculty of Biological Sciences, Medical Genetics Research Laboratory, Department of Biotechnology, Islamabad, Pakistan
                [5 ] Khyber Medical University, Institute of Basic Medical Sciences, Department of Biochemistry, Medical Genetics and Molecular Biology Unit, Peshawar, Pakistan
                Author notes
                * Address for Correspondence: Ümraniye Training and Research Hospital, Clinic of Pediatric Endocrinology, İstanbul, Turkey Phone: +90 216 632 18 18 E-mail: heveskirmizibekmez@ 123456yahoo.com
                Article
                1873
                10.4274/jcrpe.2717
                5198008
                27087618
                ac98846c-935d-4e87-b9e5-2d7c8e7030b9
                © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 December 2015
                : 5 April 2016
                Categories
                Case Report

                Pediatrics
                secondary amenorrhea,perrault syndrome,clpp
                Pediatrics
                secondary amenorrhea, perrault syndrome, clpp

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