====== NSUN3 ======

**Full name:** NOP2/Sun RNA Methyltransferase Family Member 3  
**Genomic location:** 3q21.3  
**Encodes:** A SAM-dependent mitochondrial RNA methyltransferase

===== Function =====
NSUN3 is a nuclear-encoded methyltransferase that catalyzes methylation at cytosine 34 (C34) in mitochondrial initiator tRNA^Met (mt-tRNA^Met).  
This modification produces 5-methylcytosine (m^5C), which is a prerequisite for further conversion to 5-formylcytosine (f^5C).  
f^5C is essential for mitochondrial translation initiation and efficient protein synthesis within mitochondria.

===== Pathogenic Variants =====
Biallelic pathogenic or likely pathogenic variants in *NSUN3* disrupt:
  * mt-tRNA^Met methylation
  * Mitochondrial translation
  * Oxidative phosphorylation

Resulting in a spectrum of **primary mitochondrial disorders**:
  * Isolated bilateral optic atrophy (mild)
  * Early-onset, severe multisystem mitochondrial disease (e.g., encephalomyopathy)

===== Clinical Features =====
  * Bilateral optic atrophy (nearly universal)
  * Developmental delay
  * Hypotonia
  * Failure to thrive
  * Lactic acidosis
  * Variable neurological involvement

===== Inheritance =====
  * Autosomal recessive

===== Diagnostics =====
  * Exome/genome sequencing
  * Functional studies: loss of methylation at mt-tRNA^Met
  * Muscle biopsy may show complex I/IV deficiency

===== Key References =====
  * Van Haute L, et al. Cell Reports, 2016. NSUN3 modifies mt-tRNA^Met.
  * Bugiardini E, et al. Brain, 2023. Clinical features of NSUN3 deficiency.
  * Jurkute N, et al. Invest Ophthalmol Vis Sci, 2025. Phenotypic spectrum of NSUN3 mutations.

===== Notes =====
Consider including *NSUN3* in genetic panels for:
  * Unexplained bilateral optic atrophy
  * Suspected mitochondrial disease with early-onset

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[[Visual loss]] from [[optic atrophy]] is a frequent clinical [[manifestation]] of [[mitochondrial cytopathy]]. 
Jurkute et al. aimed to identify the missing heritability in previously unsolved cases of suspected isolated or syndromic [[optic neuropathy]]. Based on three recent [[report]]s on biallelic [[NSUN3]] variants causing early-onset PMD, they explored in detail the genetic and clinical spectrum of NSUN3-associated disease.

Affected individuals were analyzed by exome or [[genome sequencing]]. In silico variant analysis and functional assays were performed to investigate the consequences of the identified variants. Detailed phenotyping data were collected from medical records and direct questioning after the identification of candidate-likely pathogenic variants.

Interrogation of exome and genome sequencing data led to the identification of six candidate NSUN3 variants in eight affected individuals from five unrelated families (including a previously reported case). A broad phenotypic spectrum was observed ranging from isolated optic atrophy to severe early-onset PMD. Identified NSUN3 variants impairing NSUN3 activity are located within the S-adenosylmethionine-dependent methyltransferases domain and loss of function variants were associated with a more severe phenotype. Remarkably, bilateral optic atrophy was a unifying clinical feature observed in almost all affected individuals.

Pathogenic or likely pathogenic biallelic variants in NSUN3 disrupt mt-tRNAMet methylation and mitochondrial translation leading to mitochondrial disease ranging from mild isolated optic atrophy to a severe multisystemic phenotype with possible limited life expectancy
((Jurkute N, Brennenstuhl H, Kustermann M, Van Haute L, Mutti CD, Bugiardini E, Handa T, Shimura M, Petzold A, Acheson J, Robson AG, Macken WL, Hanna MG, Pitceathly RDS, Merve A, Kotzaeridou U, Kölker S, Freilinger M, Erdler M, Bittner RE, Mayr JA, Okazaki Y, Murayama K, Prokisch H, Webster AR, Minczuk M, Arno G, Pemp B, Hoffmann GF, Schmidt WM, Yu-Wai-Man P. Biallelic NSUN3 Variants Cause Diverse Phenotypic Spectrum Disease: From Isolated Optic Atrophy to Severe Early-Onset Mitochondrial Disorder. Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):17. doi: 10.1167/iovs.66.6.17. PMID: 40465263.)).