RanBP-type and C3HC4-type zinc finger-containing protein 1 (also known as HOIL-1) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''RBCK1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. The protein encoded by this gene is similar to mouse UIP28/UbcM4 interacting protein. Alternative splicing has been observed at this locus, resulting in distinct isoforms. HOIL-1 is an E3 ubiquitin ligase and a part of the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase generating linear (Met1) polyubiquitin linkages. Although HOIL-1 isn’t responsible for the linear ubiquitin generation, it is a necessary component of LUBAC and ensures its proper assembly and function. Unlike most E3 ubiquitin ligases, HOIL-1 is able to catalyze oxyester bond formation between the C-terminus of a ubiquitin monomer and Ser/Thr of a different protein. This recently discovered function of HOIL-1 has so far been described in the context of MyD88 signaling. Additionally, a catalytically inactive mutant of HOIL-1 (HOIL-1^C458S) led to prolonged IKK activation and increase of inflammatory cytokine production by cytotoxic T cells. The proposed mechanism is that the ester-linked ubiquitin chains limit the size of isopeptide-linked (K63 and/or M1) ubiquitin chains.

Clinical significance

A family quartet was found with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in

proband In medical genetics and other medical fields, a proband, propositus (male proband), or proposita (female proband) is a particular subject (human or other animal) being studied or reported on. On pedigrees, the proband is noted with a square (male) ...

s in the first family.

Sanger sequencing Sanger sequencing is a method of DNA sequencing that involves electrophoresis and is based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Fred ...

identified a private homozygous

splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

in RBCK1 in the proband in the second family, yet

single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...

(SNP) genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1.

RNA-Seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...

confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products. Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified.

Clinical significance

References

Further reading