Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa

Andrea Angius, Paolo Uva, Insa Buers, Manuela Oppo, Alessandro Puddu, Stefano Onano, Ivana Persico, Angela Loi, Loredana Marcia, Wolfgang Höhne, Gianmauro Cuccuru, Giorgio Fotia, Manila Deiana, Mara Marongiu, Hatice Tuba Atalay, Sibel Inan, Osama El Assy, Leo M.E. Smit, Ilyas Okur, Koray BodurogluGülen Eda Utine, Esra Kılıç, Giuseppe Zampino, Giangiorgio Crisponi, Laura Crisponi, Frank Rutsch

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)236-245
Number of pages10
JournalAmerican Journal of Human Genetics
Publication statusPublished - 2016


  • Alleles
  • Amino Acid Sequence
  • Autoantigens
  • Child
  • Child, Preschool
  • Death, Sudden
  • Facies
  • Female
  • Genetics
  • Genetics (clinical)
  • Hand Deformities, Congenital
  • Humans
  • Hyperhidrosis
  • Infant
  • Male
  • Models, Molecular
  • Mutation
  • Pedigree
  • Phenotype
  • Retinitis Pigmentosa
  • Syndrome
  • Trismus


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