title: Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.
abstract: Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Uva
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.
authors.forename: Insa
authors.initials: I
authors.lastname: Buers
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Oppo
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Puddu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Onano
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Persico
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Loi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Marcia
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.
authors.forename: Gianmauro
authors.initials: G
authors.lastname: Cuccuru
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fotia
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Manila
authors.initials: M
authors.lastname: Deiana
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Department of Ophthalmology, Gazi University School of Medicine, 06560 Ankara, Turkey.
authors.forename: Hatice Tuba
authors.initials: HT
authors.lastname: Atalay
authors.affiliation: Opthalmology Department of Afyon Kocatepe University, 03200 Afyon, Turkey.
authors.forename: Sibel
authors.initials: S
authors.lastname: Inan
authors.affiliation: Pediatric Department-SCBU, Dibba Hospital, 11414 Dibba Al Fujaira, United Arab of Emirates.
authors.forename: Osama
authors.initials: O
authors.lastname: El Assy
authors.affiliation: Haga Ziekenhuis Den Haag, Department of Neurology, Leyweg 275, 2545 CH Den Haag, the Netherlands.
authors.forename: Leo M E
authors.initials: LM
authors.lastname: Smit
authors.affiliation: Department of Pediatric Nutrition and Metabolism, Gazi University Medical School, 06500 Ankara, Turkey.
authors.forename: Ilyas
authors.initials: I
authors.lastname: Okur
authors.affiliation: Department of Pediatrics, Division of Pediatric Genetics, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey.
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.affiliation: Department of Pediatrics, Division of Pediatric Genetics, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey.
authors.forename: Gülen Eda
authors.initials: GE
authors.lastname: Utine
authors.affiliation: Pediatric Genetics, Pediatric Hematology Oncology Research & Training Hospital, 06110 Ankara, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Kılıç
authors.affiliation: Istituto di Pediatria, Policlinico "A. Gemelli," Università Cattolica del S. Cuore, 00168 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.affiliation: Clinica Sant'Anna, 09127 Cagliari, Italy.
authors.forename: Giangiorgio
authors.initials: G
authors.lastname: Crisponi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy. Electronic address: laura.crisponi@irgb.cnr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003645:Death, Sudden; D019066:Facies; D005260:Female; D006228:Hand Deformities, Congenital / Q000150:complications* / Q000235:genetics*; D006801:Humans; D006945:Hyperhidrosis / Q000150:complications* / Q000235:genetics*; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000150:complications* / Q000235:genetics*; D013577:Syndrome; D014313:Trismus / Q000150:complications / Q000151:congenital* / Q000235:genetics
chemical_list: D001324:Autoantigens; C505353:KLHL7 protein, human