SKIV2L Mutations Cause Syndromic Diarrhea, or Trichohepatoenteric Syndrome

Fabre, Alexandre; Charroux, Bernard; Martinez-Vinson, Christine; Roquelaure, Bertrand; Eğritaş, Ödül; Sayar, Ersin; Smith, Hilary A.; Colomb, V.; André, Nicolas; Hugot, Jean‐Pierre; Goulet, Olivier; Lacoste, Caroline; Sarles, J.; Royet, Julien; Levy, Nicolas; Badens, Catherine

doi:10.1016/j.ajhg.2012.02.009

Cited by 141 publications

(129 citation statements)

References 20 publications

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“…Mutations in SKI complex genes have been linked to tricho-hepato-enteric (THE) syndrome, which causes intestinal failure (Hartley et al 2010;Fabre et al 2012Fabre et al , 2013. In addition, mutations in the DIS3 catalytic subunit gene have been implicated in multiple myeloma (Chapman et al 2011;Tomecki et al 2013;Robinson et al 2015).…”

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confidence: 99%

Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

et al. 2017

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Pontocerebellar hypoplasia type 1b (PCH1b) is an autosomal recessive disorder that causes cerebellar hypoplasia and spinal motor neuron degeneration, leading to mortality in early childhood. PCH1b is caused by mutations in the RNA exosome subunit gene, EXOSC3. The RNA exosome is an evolutionarily conserved complex, consisting of nine different core subunits, and one or two 39-59 exoribonuclease subunits, that mediates several RNA degradation and processing steps. The goal of this study is to assess the functional consequences of the amino acid substitutions that have been identified in EXOSC3 in PCH1b patients. To analyze these EXOSC3 substitutions, we generated the corresponding amino acid substitutions in the Saccharomyces cerevisiae ortholog of EXOSC3, Rrp40. We find that the rrp40 variants corresponding to EXOSC3-G31A and -D132A do not affect yeast function when expressed as the sole copy of the essential Rrp40 protein. In contrast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b patients, impacts cell growth and RNA exosome function when expressed as the sole copy of Rrp40. The rrp40-W195R protein is unstable, and does not associate efficiently with the RNA exosome in cells that also express wild-type Rrp40. Consistent with these findings in yeast, the levels of mouse EXOSC3 variants are reduced compared to wild-type EXOSC3 in a neuronal cell line. These data suggest that cells possess a mechanism for optimal assembly of functional RNA exosome complex that can discriminate between wildtype and variant exosome subunits. Budding yeast can therefore serve as a useful tool to understand the molecular defects in the RNA exosome caused by PCH1b-associated amino acid substitutions in EXOSC3, and potentially extending to disease-associated substitutions in other exosome subunits.KEYWORDS pontocerebellar hypoplasia type 1b; RNA exosome; EXOSC3; Rrp40; EXOSC2; RNA processing/degradation T HE RNA exosome is an evolutionarily conserved ribonuclease complex that is responsible for several essential RNA processing and degradation steps (Mitchell et al. 1997;Allmang et al. 1999;Schneider and Tollervey 2013). Major exosome substrates include mRNA, rRNA, and small RNAs. In addition to degrading aberrant and unneeded transcripts, the RNA exosome also trims precursor RNAs, including 5.8S rRNA (Mitchell et al. 1996). The RNA exosome thus plays critical roles in both RNA degradation and maturation.The subunits of the RNA exosome complex are evolutionarily conserved and many were first identified in Saccharomyces cerevisiae in a screen for ribosomal RNA processing (rrp) mutants (Mitchell et al. 1996(Mitchell et al. , 1997Allmang et al. 1999). S. cerevisiae Rrp subunits correspond to human EXOSC subunits. The functions of the RNA exosome have been extensively characterized in budding yeast (Sloan et al. 2012), and many are conserved in humans (Schilders et al. 2005;Staals et al. 2010;Lubas et al. 2011Lubas et al. , 2015 the RNA exosome, six subunits comprise a core ring, and three putative RNA-binding sub...

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confidence: 99%

Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

et al. 2017

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“…Buscaron mutaciones en el gen ortólogo humano de SKI3 que resultó en la identificación de mutaciones deletéreas en el gen SKIV2L en los seis individuos referidos. 5 En el Cuadro 1 se resumen los hallazgos de estos autores con los datos observados en nuestra paciente. Ellos mismos señalan otro gen candidato para los casos potenciales donde la pesquisa de mutaciones conocidas sea negativa: el gen WDR61, ortólogo humano del tercer cofactor SKI8.…”

Section: Discussionunclassified

Diarrea crónica intratable asociada con diarrea fenotípica de la infancia (síndrome tricohepatoentérico)

Cadena-León¹,

Rodrı́guez-Jurado

2014

Acta Pediatr Mex

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“…Two are very frequent (more than 90%): IUGR and immunodeficiency; 2 are frequent: skin abnormalities and liver disease and 2 are rare: congenital cardiac defects and platelet anomaly. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The phenotypic presentation of THE-S is heterogeneous, and ranges from mild to severe form, which is characterized with long-term parenteral nutrition, and in some patients, typically it lasts for months to years, to achieve adequate nutrition and growth. 12 However, longterm parenteral nutrition should not be started in patients with concomitant liver disease.…”

Section: Discussionmentioning

confidence: 99%

“…1 44 cases have been published between 1982 and 2012. Literature reviewed showed that 9 clinical signs are associated with THE-S. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] Three are constant: intractable diarrhea, facial dysmorphism and hair abnormality. Two are very frequent (more than 90%): IUGR and immunodeficiency; 2 are frequent: skin abnormalities and liver disease and 2 are rare: congenital cardiac defects and platelet anomaly.…”

Section: Discussionmentioning

confidence: 99%