Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

TY - JOUR

T1 - Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

AU - Woldegebriel, Rosa

AU - Kvist, Jouni

AU - Andersson, Noora

AU - Õunap, Katrin

AU - Reinson, Karit

AU - Wojcik, Monica H

AU - Bijlsma, Emilia K

AU - Hoffer, Mariëtte J V

AU - Ryan, Monique M

AU - Stark, Zornitza

AU - Walsh, Maie

AU - Cuppen, Inge

AU - van den Boogaard, Marie-Jose H

AU - Bharucha-Goebel, Diana

AU - Donkervoort, Sandra

AU - Winchester, Sara

AU - Zori, Roberto

AU - Bönnemann, Carsten G

AU - Maroofian, Reza

AU - O'Connor, Emer

AU - Houlden, Henry

AU - Zhao, Fang

AU - Carpén, Olli

AU - White, Matthew

AU - Sreedharan, Jemeen

AU - Stewart, Murray

AU - Ylikallio, Emil

AU - Tyynismaa, Henna

N1 - © The Author(s) 2020. Published by Oxford University Press.

PY - 2020/6/3

Y1 - 2020/6/3

N2 - Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content dependent regulation of gene expression. For example all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease, and suggest mechanisms by which GANP defects might alter RNA metabolism.

AB - Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content dependent regulation of gene expression. For example all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease, and suggest mechanisms by which GANP defects might alter RNA metabolism.

UR - http://www.scopus.com/inward/record.url?scp=85086051014&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddaa051

DO - 10.1093/hmg/ddaa051

M3 - Article

C2 - 32202298

SN - 0964-6906

VL - 29

SP - 1426

EP - 1439

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

ER -