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.
Lingua originale | English |
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pagine (da-a) | 236-245 |
Numero di pagine | 10 |
Rivista | American Journal of Human Genetics |
Volume | 99 |
DOI | |
Stato di pubblicazione | Pubblicato - 2016 |
Keywords
- 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