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: [email protected].
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.