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Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.
Am J Hum Genet. 2016 Jul 07; 99(1):236-45.AJ

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+Show Affiliations

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.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.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.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.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.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.Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.Department of Ophthalmology, Gazi University School of Medicine, 06560 Ankara, Turkey.Opthalmology Department of Afyon Kocatepe University, 03200 Afyon, Turkey.Pediatric Department-SCBU, Dibba Hospital, 11414 Dibba Al Fujaira, United Arab of Emirates.Haga Ziekenhuis Den Haag, Department of Neurology, Leyweg 275, 2545 CH Den Haag, the Netherlands.Department of Pediatric Nutrition and Metabolism, Gazi University Medical School, 06500 Ankara, Turkey.Department of Pediatrics, Division of Pediatric Genetics, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey.Department of Pediatrics, Division of Pediatric Genetics, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey.Pediatric Genetics, Pediatric Hematology Oncology Research & Training Hospital, 06110 Ankara, Turkey.Istituto di Pediatria, Policlinico "A. Gemelli," Università Cattolica del S. Cuore, 00168 Rome, Italy.Clinica Sant'Anna, 09127 Cagliari, Italy.Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy. Electronic address: laura.crisponi@irgb.cnr.it.Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

27392078

Citation

Angius, Andrea, et al. "Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated With Early-Onset Retinitis Pigmentosa." American Journal of Human Genetics, vol. 99, no. 1, 2016, pp. 236-45.
Angius A, Uva P, Buers I, et al. Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. Am J Hum Genet. 2016;99(1):236-45.
Angius, A., Uva, P., Buers, I., Oppo, M., Puddu, A., Onano, S., Persico, I., Loi, A., Marcia, L., Höhne, W., Cuccuru, G., Fotia, G., Deiana, M., Marongiu, M., Atalay, H. T., Inan, S., El Assy, O., Smit, L. M., Okur, I., ... Rutsch, F. (2016). Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. American Journal of Human Genetics, 99(1), 236-45. https://doi.org/10.1016/j.ajhg.2016.05.026
Angius A, et al. Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated With Early-Onset Retinitis Pigmentosa. Am J Hum Genet. 2016 Jul 7;99(1):236-45. PubMed PMID: 27392078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. AU - Angius,Andrea, AU - Uva,Paolo, AU - Buers,Insa, AU - Oppo,Manuela, AU - Puddu,Alessandro, AU - Onano,Stefano, AU - Persico,Ivana, AU - Loi,Angela, AU - Marcia,Loredana, AU - Höhne,Wolfgang, AU - Cuccuru,Gianmauro, AU - Fotia,Giorgio, AU - Deiana,Manila, AU - Marongiu,Mara, AU - Atalay,Hatice Tuba, AU - Inan,Sibel, AU - El Assy,Osama, AU - Smit,Leo M E, AU - Okur,Ilyas, AU - Boduroglu,Koray, AU - Utine,Gülen Eda, AU - Kılıç,Esra, AU - Zampino,Giuseppe, AU - Crisponi,Giangiorgio, AU - Crisponi,Laura, AU - Rutsch,Frank, PY - 2016/02/09/received PY - 2016/05/19/accepted PY - 2016/7/9/entrez PY - 2016/7/9/pubmed PY - 2017/5/20/medline SP - 236 EP - 45 JF - American journal of human genetics JO - Am J Hum Genet VL - 99 IS - 1 N2 - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/27392078/Bi_allelic_Mutations_in_KLHL7_Cause_a_Crisponi/CISS1_like_Phenotype_Associated_with_Early_Onset_Retinitis_Pigmentosa_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(16)30161-6 DB - PRIME DP - Unbound Medicine ER -