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. doi: 10.1016/j.ajhg.2016.05.026.

Andrea Angius ¹, Paolo Uva ², Insa Buers ³, Manuela Oppo ⁴, Alessandro Puddu ¹, Stefano Onano ⁴, Ivana Persico ¹, Angela Loi ¹, Loredana Marcia ⁴, Wolfgang Höhne ⁵, Gianmauro Cuccuru ², Giorgio Fotia ², Manila Deiana ¹, Mara Marongiu ¹, Hatice Tuba Atalay ⁶, Sibel Inan ⁷, Osama El Assy ⁸, Leo M E Smit ⁹, Ilyas Okur ¹⁰, Koray Boduroglu ¹¹, Gülen Eda Utine ¹¹, Esra Kılıç ¹², Giuseppe Zampino ¹³, Giangiorgio Crisponi ¹⁴, Laura Crisponi ¹⁵, Frank Rutsch ³

Affiliations

1 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
2 Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, 09010 Pula, Italy.
3 Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.
4 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.
5 Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
6 Department of Ophthalmology, Gazi University School of Medicine, 06560 Ankara, Turkey.
7 Opthalmology Department of Afyon Kocatepe University, 03200 Afyon, Turkey.
8 Pediatric Department-SCBU, Dibba Hospital, 11414 Dibba Al Fujaira, United Arab of Emirates.
9 Haga Ziekenhuis Den Haag, Department of Neurology, Leyweg 275, 2545 CH Den Haag, the Netherlands.
10 Department of Pediatric Nutrition and Metabolism, Gazi University Medical School, 06500 Ankara, Turkey.
11 Department of Pediatrics, Division of Pediatric Genetics, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey.
12 Pediatric Genetics, Pediatric Hematology Oncology Research & Training Hospital, 06110 Ankara, Turkey.
13 Istituto di Pediatria, Policlinico "A. Gemelli," Università Cattolica del S. Cuore, 00168 Rome, Italy.
14 Clinica Sant'Anna, 09127 Cagliari, Italy.
15 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy. Electronic address: laura.crisponi@irgb.cnr.it.

PMID: 27392078 DOI: 10.1016/j.ajhg.2016.05.026

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.

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