DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes

in European Journal of Endocrinology
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  • 1 ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
  • 2 Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
  • 3 Université de Paris, Faculté de Médecine Paris-Diderot, Inserm U958, Paris, France
  • 4 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, Commissariat à l’Energie Atomique, Université Paris-Saclay, Evry, France
  • 5 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  • 6 Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
  • 7 Division of Pediatric Endocrinology, Lyon 1 University, Lyon, France
  • 8 IRCAN, UMR CNRS 7284/Inserm U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice, France
  • 9 Department of Medical Genetics, Nice Teaching Hospital, National Centre for Mitochondrial Diseases, Nice, France

Correspondence should be addressed to C Julier or M Cnop; Email: cecile.julier@inserm.fr or mcnop@ulb.ac.be

*(M Lytrivi, V Senée, P Salpea and F Fantuzzi contributed equally to this work as first authors)

(V Senée, A Philippi and A Degavre are now at Université de Paris, Institut Cochin, Inserm U1016, Paris, France)

(C Julier and M Cnop contributed equally as senior authors)

Objective

DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome.

Methods

Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined.

Results

The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA.

Conclusions

This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.

Supplementary Materials

    • Supplemental Table 1: DNAJC3 Sanger sequencing primers
    • Supplemental Table 2: PCR-RFLP genotyping assays for two DNAJC3 variants
    • Supplemental Table 3: Primers used for qPCR
    • Supplemental Table 4: Primary and secondary antibodies
    • Supplemental Figure 1: Brain MRI of patient 1, showing severe cerebellar hypoplasia with midbrain atrophy. (A) Coronal T2-weighted image showing severe cerebellar atrophy. (B) Sagittal T1-weighted image showing severe hypoplasia of the vermis with mildly atrophic brainstem.
    • Supplemental Figure 2: Clinical and genetic characteristics of family 1. Diabetic proband is shown in black symbol (arrow). Diabetes status in the nuclear family (parents and children) was established based on fasting glucose and HbA1c levels (see Figure 1). Diabetes status and stature of distant relatives are based on family history, revealing a high proportion of subjects with adult-onset diabetes (dark grey symbols); these relatives were not available for genetic study. +: reference allele; p.M1V and p.R346*: DNAJC3 mutated alleles.
    • Supplemental Figure 3: Confirmation of the impact of DNAJC3 silencing on β-cell function and apoptosis using a second siRNA. INS-1E or dispersed human islet cells were transfected with control siRNA (siCT) or a second siRNA targeting DNAJC3 (siDNAJC3 #2). (A) Dnajc3 mRNA levels in INS-1E cells after transfection (n=3). (B) Insulin secretion (left panel) was induced by 1.67 or 16.7 mM glucose 48h after transfection, and expressed as percent of insulin content. INS-1E cell insulin content (right panel) is corrected for total protein (n=5). (C-D). Apoptosis was examined by propidium iodide and Hoechst 33342 staining in INS-1E cells (n=4) (C) and dispersed human islet cells (n=5) (D) transfected with siCT or siDNAJC3 #2. *p<0.05, **p<0.01 vs siCT and ##p<0.01 vs 1.67 mM glucose.
    • Supplemental Figure 4: Bad, PUMA or DP5 do not mediate mitochondrial apoptosis due to DNAJC3 deficiency. INS-1E cells were transfected with siCT or Dnajc3 siRNA, alone or together with siRNA targeting Bad (A, n=5), PUMA (B, n=3-5) or DP5 (C, n=4-6). Cells were then treated with CPA or control (CTL) for 16h. Left panels show Bad, Puma and DP5 mRNA expression and right panels show apoptosis in the same experimental conditions, as examined by propidium iodide and Hoechst 33342 staining. *p<0.05, **p<0.01, *** p<0.001 vs siCT and #p<0.05, ##p<0.01 and ###p<0.001 vs non-treated cells.
    • Supplemental Figure 5: Characterization of control iPSC line 1023.A. The iPSCs 1023.A from a healthy donor showed (A) normal karyotype visualized with G-banding, (B) classical iPSC morphology visualized with bright-field microscopy and (C) expression of the pluripotency markers OCT4 (green), SSEA4 (green) and TRA-1-60 (green) by immunofluorescent staining. Nuclei were stained with DAPI (blue).
    • Supplemental Figure 6: Characterization of control iPSC line HEL185.3. The iPSCs HEL185.3 from a healthy donor showed (A) normal karyotype visualized with G-banding, (B) classical iPSC morphology visualized with bright-field microscopy and (C) expression of the pluripotency markers OCT4 (green), SSEA4 (green) and TRA-1-60 (green) by immunofluorescent staining. Nuclei were stained with DAPI (blue).
    • Supplemental Figure 7: DNAJC3, BIM and PUMA silencing in iPSC-derived β-cells. iPSC-derived β-cells were transfected with control siRNA (siCT) or siRNA targeting DNAJC3, alone or together with siRNA targeting BIM (A-B) or PUMA (C-D). Cells were then treated with thapsigargin or control (CTL) for 48h. DNACJ3 (A, C), BIM (B) and PUMA (D) mRNA expression was assessed by qPCR and normalized to the geometric mean of the reference genes GAPDH and ACTB (n=5). *p<0.05, **p<0.01, ***p<0.001 vs siCT, ###p<0.001 vs non-treated cells.

 

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