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

• Published in: American journal of human genetics Vol. 99; no. 1; pp. 236 - 245
• Main Authors: Angius, Andrea, Uva, Paolo, Buers, Insa, Oppo, Manuela, Puddu, Alessandro, Onano, Stefano, Persico, Ivana, Loi, Angela, Marcia, Loredana, Höhne, Wolfgang, Cuccuru, Gianmauro, Fotia, Giorgio, Deiana, Manila, Marongiu, Mara, Atalay, Hatice Tuba, Inan, Sibel, El Assy, Osama, Smit, Leo M.E., Okur, Ilyas, Boduroglu, Koray, Utine, Gülen Eda, Kılıç, Esra, Zampino, Giuseppe, Crisponi, Giangiorgio, Crisponi, Laura, Rutsch, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-07-2016; Cell Press; Elsevier
• Subjects: Alleles; Amino Acid Sequence; Autoantigens - chemistry; Autoantigens - genetics; Blindness; Child; Child, Preschool; Death, Sudden; Eye diseases; Facies; Female; Genotype & phenotype; Hand Deformities, Congenital - complications; Hand Deformities, Congenital - genetics; Humans; Hyperhidrosis - complications; Hyperhidrosis - genetics; Infant; Male; Models, Molecular; Mutation; Newborn babies; Pedigree; Phenotype; Retinitis Pigmentosa - complications; Retinitis Pigmentosa - genetics; Syndrome; Trismus - complications; Trismus - congenital; Trismus - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2016.05.026

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.