Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes.
Abnormalities, Multiple
/ genetics
Alleles
Animals
Consanguinity
Ellis-Van Creveld Syndrome
/ diagnostic imaging
Gene Knockout Techniques
Gestational Age
Humans
Infant, Premature, Diseases
/ genetics
Loss of Function Mutation
Magnetic Resonance Imaging
Male
Mice
Pedigree
Protein Disulfide-Isomerases
/ genetics
Unfolded Protein Response
/ genetics
PDIA6
asphyxiating thoracic dystrophy
diabetes, narrow thorax
immunodeficiency
polycystic kidney disease
unfolded protein response
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
18
01
2021
received:
19
12
2020
accepted:
21
01
2021
pubmed:
27
1
2021
medline:
1
2
2022
entrez:
26
1
2021
Statut:
ppublish
Résumé
Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)-regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage-dependent manner, supporting a loss-of-function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin-dependent diabetes for variants in PDIA6.
Substances chimiques
PDIA6 protein, human
EC 5.3.4.1
Protein Disulfide-Isomerases
EC 5.3.4.1
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
694-703Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Kikuchi M, Doi E, Tsujimoto I, Horibe T, Tsujimoto Y. Functional analysis of human P5, a protein disulfide isomerase homologue. J Biochem. 2002;132:451-455. https://doi.org/10.1093/oxfordjournals.jbchem.a003242.
Laurindo FRM, Pescatore LA, De Castro Fernandes D. Protein disulfide isomerase in redox cell signaling and homeostasis. Free Radic Biol Med. 2012;52:1954-1969. https://doi.org/10.1016/j.freeradbiomed.2012.02.037.
Choi JH, Zhong X, Zhang Z, et al. Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development. J Exp Med. 2020;217:e20190006. https://doi.org/10.1084/jem.20190006.
Eletto D, Eletto D, Dersh D, Gidalevitz T, Argon Y. Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Mol Cell. 2014;53:562-576. https://doi.org/10.1016/j.molcel.2014.01.004.
Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One. 2009;4:e4170. https://doi.org/10.1371/journal.pone.0004170.
Gorasia DG, Dudek NL, Safavi-Hemami H, et al. A prominent role of PDIA6 in processing of misfolded proinsulin. Biochim Biophys Acta - Proteins Proteomics. 2016;1864:715-723. https://doi.org/10.1016/j.bbapap.2016.03.002.
Jordan PA, Stevens JM, Hubbard GP, et al. A role for the thiol isomerase protein ERP5 in platelet function. Blood. 2005;105:1500-1507. https://doi.org/10.1182/blood-2004-02-0608.
Passam FH, Lin L, Gopal S, et al. Both platelet- and endothelial cell-derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis. Blood. 2015;125:2276-2285. https://doi.org/10.1182/blood-2013-12-547208.
Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ. The unfolded protein response sensor IRE1α is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest. 2005;115:268-281. https://doi.org/10.1172/jci21848.
Iwawaki T, Akai R, Yamanaka S, Kohno K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A. 2009;106:16657-16662. https://doi.org/10.1073/pnas.0903775106.
Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7:1153-1163. https://doi.org/10.1016/S1097-2765(01)00264-7.
Zhang P, McGrath B, Li S, et al. The PERK eukaryotic initiation factor 2α kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol. 2002;22:3864-3874. https://doi.org/10.1128/mcb.22.11.3864-3874.2002.
Delépine M, Nicolino M, Barrett T, Golamaully M, Mark Lathrop G, Julier C. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000;25:406-409. https://doi.org/10.1038/78085.
Durocher F, Faure R, Labrie Y, Pelletier L, Bouchard I, Laframboise R. A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome. Clin Genet. 2006;70:34-38. https://doi.org/10.1111/j.1399-0004.2006.00632.x.
Fatani TH. EIF2AK3 novel mutation in a child with early-onset diabetes mellitus, a case report. BMC Pediatr. 2019;19:85. https://doi.org/10.1186/s12887-019-1432-8.
Alhebbi H, Peer-Zada AA, Al-Hussaini AA, et al. New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. J Hum Genet. 2020;66:151-159. https://doi.org/10.1038/s10038-020-0811-1.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. https://doi.org/10.1038/gim.2015.30.
Abdulwahab F, Abouelhoda M, Abouthuraya R, et al. Erratum to: comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases [Genome Biol. 16, (2015), 134]. Genome Biol. 2015;16:226. https://doi.org/10.1186/s13059-015-0798-7.
Abouelhoda M, Sobahy T, El-Kalioby M, et al. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. Genet Med. 2016;18:1244-1249. https://doi.org/10.1038/gim.2016.37.
Wang T, Zhan X, Bua CH, et al. Real-time resolution of point mutations that cause phenovariance in mice. Proc Natl Acad Sci U S A. 2015;112:E440-E449. https://doi.org/10.1073/pnas.1423216112.
Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281-2308. https://doi.org/10.1038/nprot.2013.143.
De Vries J, Yntema JL, Van Die CE, Crama N, Cornelissen EAM, Hamel BCJ. Jeune syndrome: description of 13 cases and a proposal for follow-up protocol. Eur J Pediatr. 2010;169:77-88. https://doi.org/10.1007/s00431-009-0991-3.
Baujat G, Huber C, El Hokayem J, et al. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013;50:91-98. https://doi.org/10.1136/jmedgenet-2012-101282.
Beales PL, Bland E, Tobin JL, et al. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007;39:727-729. https://doi.org/10.1038/ng2038.
Bredrup C, Saunier S, Oud MM, et al. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet. 2011;89:634-643. https://doi.org/10.1016/j.ajhg.2011.10.001.
Dagoneau N, Goulet M, Geneviève D, et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009;84:706-711. https://doi.org/10.1016/j.ajhg.2009.04.016.
Davis EE, Zhang Q, Liu Q, et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011;43:189-196. https://doi.org/10.1038/ng.756.
Perrault I, Saunier S, Hanein S, et al. Mainzer-saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet. 2012;90:864-870. https://doi.org/10.1016/j.ajhg.2012.03.006.
Meunier L, Usherwood YK, Tae Chung K, Hendershot LM. A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell. 2002;13:4456-4469. https://doi.org/10.1091/mbc.E02-05-0311.
Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326-332. https://doi.org/10.1038/35014014.
Yu M, Haslam RHA, Haslam DB. HEDJ, an Hsp40 co-chaperone localized to the endoplasmic reticulum of human cells. J Biol Chem. 2000;275:24984-24992. https://doi.org/10.1074/jbc.M000739200.
Cornec-Le Gall E, Olson RJ, Besse W, et al. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. Am J Hum Genet. 2018;102:832-844. https://doi.org/10.1016/j.ajhg.2018.03.013.
Noiva R, Lennarz WJ. Protein disulfide isomerase. A multifunctional protein resident in the lumen of the endoplasmic reticulum. J Biol Chem. 1992;267:3553-3556.
David Cole EC, Carpenter TO. Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr. 1987;110:76-80. https://doi.org/10.1016/S0022-3476(87)80292-5.
Rauch F, Fahiminiya S, Majewski J, et al. Cole-carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am J Hum Genet. 2015;96:425-431. https://doi.org/10.1016/j.ajhg.2014.12.027.
Woods KA, Camacho-Hübner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996;335:1363-1367. https://doi.org/10.1056/nejm199610313351805.