Neonatal diabetes mellitus is a significant feature of COXPD-24 caused by recessive NARS2 variants
Diabetic Medicine, cilt.42, sa.11, 2025 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 42 Sayı: 11
- Basım Tarihi: 2025
- Doi Numarası: 10.1111/dme.70129
- Dergi Adı: Diabetic Medicine
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, CINAHL, EMBASE, MEDLINE
- Anahtar Kelimeler: mitochondria, mitochondrial disease, mitochondrial dysfunction, monogenic diabetes, NARS2, neonatal diabetes mellitus, beta-Cells
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
Background: Recessive loss-of-function NARS2 variants causing the multi-system disorder Combined oxidative phosphorylation deficiency 24 (COXPD24) have recently been reported in 3 individuals with diabetes diagnosed between 3 days and 14 months of age. In this study, we investigate the presence of NARS2 variants in a large cohort of individuals with early-onset diabetes. Methods: We used genome and targeted next-generation sequencing to screen for rare, coding biallelic NARS2 variants in a cohort of 397 individuals diagnosed with diabetes <24 months of age of unknown genetic cause. Results: We identified 8 individuals with homozygous disease-causing missense variants in NARS2 (4 individuals with the p.(Phe216Leu) variant, 3 with p.(Thr180Asn) and one with p.(Val440Leu)). All 8 individuals were diagnosed with insulin-dependent diabetes before 6 months of age (neonatal diabetes, NDM) with the median age at diagnosis being 4 weeks (range: 1 to 20 weeks). 7/8 probands had low birthweight (median Z-score: −2.43, range: −4.17 to 0.86). Neurological features were common, with epilepsy and developmental delay each identified in 7/8 and 6/8 participants, respectively. Conclusion: Taken together with previously published cases, this study shows that NDM is an important feature of COXPD-24 and highlights a critical role for NARS2 in the insulin-secreting pancreatic β-cell.