Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6

Jamie Trott, Yunus Alpagu, Ee Kim Tan, Mohammad Shboul, Yousif Dawood, Michael Elsy, Heike Wollmann, Vincent Tano, Carine Bonnard, Shermaine Eng, Gunaseelan Narayanan, Seetanshu Junnarkar, Stephen Wearne, James Strutt, Aakash Kumar, Lucian B. Tomaz, Pierre Alexis Goy, Slim Mzoughi, Rachel Jennings, Jaco HagoortAscia Eskin, Hane Lee, Stanley F. Nelson, Fawaz Al-Kazaleh, Mohammad El-Khateeb, Rajaa Fathallah, Harsha Shah, Jonathan Goeke, Sarah R. Langley, Ernesto Guccione, Neil Hanley, Bernadette S. de Bakker, Bruno Reversade, N. Ray Dunn

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Mitchell-Riley syndrome (MRS) is caused by recessive mutations in the regulatory factor X6 gene (RFX6) and is characterised by pancreatic hypoplasia and neonatal diabetes. To determine why individuals with MRS specifically lack pancreatic endocrine cells, we micro-CT imaged a 12-week-old foetus homozygous for the nonsense mutation RFX6 c.1129C>T, which revealed loss of the pancreas body and tail. From this foetus, we derived iPSCs and show that differentiation of these cells in vitro proceeds normally until generation of pancreatic endoderm, which is significantly reduced. We additionally generated an RFX6HA reporter allele by gene targeting in wild-type H9 cells to precisely define RFX6 expression and in parallel performed in situ hybridisation for RFX6 in the dorsal pancreatic bud of a Carnegie stage 14 human embryo. Both in vitro and in vivo, we find that RFX6 specifically labels a subset of PDX1-expressing pancreatic endoderm. In summary, RFX6 is essential for efficient differentiation of pancreatic endoderm, and its absence in individuals with MRS specifically impairs formation of endocrine cells of the pancreas head and tail.
Original languageEnglish (US)
JournalDevelopment (Cambridge)
Issue number21
StatePublished - Nov 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology


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