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Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice.

Siggs OM, Grieve A, Xu H, Bambrough P, Christova Y, Freeman M - Biol Open (2014)

Bottom Line: In mammals iRhoms are known to regulate the trafficking of TACE, the protease that cleaves the membrane bound inflammatory cytokine TNF.We have also identified a previously reported suppressor of cub, called Mcub (modifier of curly bare), and find it to be a loss of function allele of the amphiregulin gene (Areg).Our results do not support this hypothesis: we find that, compared to wild-type cells, cub mutant embryonic fibroblasts release less amphiregulin, and that the cub mutant form of iRhom2 is less able than wild type to bind to TACE and promote its maturation.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

No MeSH data available.


Related in: MedlinePlus

cub and Mcub are mutations at the Rhbdf2 and Areg loci, respectively.(A) Coverage depth across the Rhbdf2 locus in cub/cub mice, and predicted translational consequences of the cub deletion on iRhom2 protein. (B) Filtering pipeline for variants detected after whole-genome sequencing of cub/cub;Mcub/Mcub DNA. (C) Identification and predicted consequences of the AregMcub variant. (D) The bald phenotype of an Rhbdf2cub/Rhbdf2cub mouse (Johnson et al., 2003). (E) Rhbdf2KO/Rhbdf2KO mouse has a WT coat (Adrain et al., 2012; McIlwain et al., 2012). (F) Rhbdf2cub is recessive: Rhbdf2cub/+ mouse has a WT coat (Johnson et al., 2003). (G) Rhbdf2cub/Rhbdf2KO mouse has sparse hair (Hosur et al., 2014). Mice in panels D–G are on a C57BL/6J background, except for Rhbdf2cub/Rhbdf2KO, which is on a mixed C57BL/6J/129 background.
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f01: cub and Mcub are mutations at the Rhbdf2 and Areg loci, respectively.(A) Coverage depth across the Rhbdf2 locus in cub/cub mice, and predicted translational consequences of the cub deletion on iRhom2 protein. (B) Filtering pipeline for variants detected after whole-genome sequencing of cub/cub;Mcub/Mcub DNA. (C) Identification and predicted consequences of the AregMcub variant. (D) The bald phenotype of an Rhbdf2cub/Rhbdf2cub mouse (Johnson et al., 2003). (E) Rhbdf2KO/Rhbdf2KO mouse has a WT coat (Adrain et al., 2012; McIlwain et al., 2012). (F) Rhbdf2cub is recessive: Rhbdf2cub/+ mouse has a WT coat (Johnson et al., 2003). (G) Rhbdf2cub/Rhbdf2KO mouse has sparse hair (Hosur et al., 2014). Mice in panels D–G are on a C57BL/6J background, except for Rhbdf2cub/Rhbdf2KO, which is on a mixed C57BL/6J/129 background.

Mentions: To identify the nature of the cub and Mcub mutations (Johnson et al., 2003), we sequenced the genome of a cub/cub;Mcub/Mcub double homozygote. cub arose spontaneously within an inbred colony of urogenital syndrome (us) mice at the Jackson Laboratory (a/a us/us), and has previously been mapped to a 75-gene interval between D11Mit214 and D11Mit303 (chr11:115130471–117238606) (Johnson et al., 2003). Interestingly, a similar phenotype, Uncovered, has also been mapped between D11Mit338 and D11Mit337 (chr11:115461783–118997798) (Shi et al., 2003). Although we detected no single nucleotide variants or short indels in the cub interval, a large deletion was present at the Rhbdf2 locus (Fig. 1A). The Rhbdf2cub deletion spanned 12,679 nucleotides (chr11: 116604896–116617574, inclusive), which included exons 2–6. This deletion is predicted to result in the splicing of exon 1 to exon 7, the initiation of translation from an in-frame methionine codon in exon 8, and therefore the loss of the first 268 N-terminal residues, which include almost the entire cytoplasmic domain of iRhom2 (Fig. 1A).


Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice.

Siggs OM, Grieve A, Xu H, Bambrough P, Christova Y, Freeman M - Biol Open (2014)

cub and Mcub are mutations at the Rhbdf2 and Areg loci, respectively.(A) Coverage depth across the Rhbdf2 locus in cub/cub mice, and predicted translational consequences of the cub deletion on iRhom2 protein. (B) Filtering pipeline for variants detected after whole-genome sequencing of cub/cub;Mcub/Mcub DNA. (C) Identification and predicted consequences of the AregMcub variant. (D) The bald phenotype of an Rhbdf2cub/Rhbdf2cub mouse (Johnson et al., 2003). (E) Rhbdf2KO/Rhbdf2KO mouse has a WT coat (Adrain et al., 2012; McIlwain et al., 2012). (F) Rhbdf2cub is recessive: Rhbdf2cub/+ mouse has a WT coat (Johnson et al., 2003). (G) Rhbdf2cub/Rhbdf2KO mouse has sparse hair (Hosur et al., 2014). Mice in panels D–G are on a C57BL/6J background, except for Rhbdf2cub/Rhbdf2KO, which is on a mixed C57BL/6J/129 background.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265752&req=5

f01: cub and Mcub are mutations at the Rhbdf2 and Areg loci, respectively.(A) Coverage depth across the Rhbdf2 locus in cub/cub mice, and predicted translational consequences of the cub deletion on iRhom2 protein. (B) Filtering pipeline for variants detected after whole-genome sequencing of cub/cub;Mcub/Mcub DNA. (C) Identification and predicted consequences of the AregMcub variant. (D) The bald phenotype of an Rhbdf2cub/Rhbdf2cub mouse (Johnson et al., 2003). (E) Rhbdf2KO/Rhbdf2KO mouse has a WT coat (Adrain et al., 2012; McIlwain et al., 2012). (F) Rhbdf2cub is recessive: Rhbdf2cub/+ mouse has a WT coat (Johnson et al., 2003). (G) Rhbdf2cub/Rhbdf2KO mouse has sparse hair (Hosur et al., 2014). Mice in panels D–G are on a C57BL/6J background, except for Rhbdf2cub/Rhbdf2KO, which is on a mixed C57BL/6J/129 background.
Mentions: To identify the nature of the cub and Mcub mutations (Johnson et al., 2003), we sequenced the genome of a cub/cub;Mcub/Mcub double homozygote. cub arose spontaneously within an inbred colony of urogenital syndrome (us) mice at the Jackson Laboratory (a/a us/us), and has previously been mapped to a 75-gene interval between D11Mit214 and D11Mit303 (chr11:115130471–117238606) (Johnson et al., 2003). Interestingly, a similar phenotype, Uncovered, has also been mapped between D11Mit338 and D11Mit337 (chr11:115461783–118997798) (Shi et al., 2003). Although we detected no single nucleotide variants or short indels in the cub interval, a large deletion was present at the Rhbdf2 locus (Fig. 1A). The Rhbdf2cub deletion spanned 12,679 nucleotides (chr11: 116604896–116617574, inclusive), which included exons 2–6. This deletion is predicted to result in the splicing of exon 1 to exon 7, the initiation of translation from an in-frame methionine codon in exon 8, and therefore the loss of the first 268 N-terminal residues, which include almost the entire cytoplasmic domain of iRhom2 (Fig. 1A).

Bottom Line: In mammals iRhoms are known to regulate the trafficking of TACE, the protease that cleaves the membrane bound inflammatory cytokine TNF.We have also identified a previously reported suppressor of cub, called Mcub (modifier of curly bare), and find it to be a loss of function allele of the amphiregulin gene (Areg).Our results do not support this hypothesis: we find that, compared to wild-type cells, cub mutant embryonic fibroblasts release less amphiregulin, and that the cub mutant form of iRhom2 is less able than wild type to bind to TACE and promote its maturation.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

No MeSH data available.


Related in: MedlinePlus