Publication: Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.
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Date
2018-05-04
Authors
Frints, Suzanna G M
Ozanturk, Aysegul
Rodríguez Criado, Germán
Grasshoff, Ute
de Hoon, Bas
Field, Michael
Manouvrier-Hanu, Sylvie
E Hickey, Scott
Kammoun, Molka
Gripp, Karen W
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Abstract
RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.
Description
MeSH Terms
Adolescent
Adult
Animals
Child
Child, Preschool
Conduct Disorder
Female
Genes, X-Linked
HEK293 Cells
Humans
Infant, Newborn
Intellectual Disability
Male
Mental Retardation, X-Linked
Mice
Middle Aged
Mutation
Pedigree
Transcription Factors
Ubiquitin-Protein Ligases
Ubiquitination
X Chromosome Inactivation
Zebrafish
Zebrafish Proteins
Adult
Animals
Child
Child, Preschool
Conduct Disorder
Female
Genes, X-Linked
HEK293 Cells
Humans
Infant, Newborn
Intellectual Disability
Male
Mental Retardation, X-Linked
Mice
Middle Aged
Mutation
Pedigree
Transcription Factors
Ubiquitin-Protein Ligases
Ubiquitination
X Chromosome Inactivation
Zebrafish
Zebrafish Proteins