NADSYN1

The NADSYN1 gene encodes NAD synthetase 1, a cytosolic enzyme that catalyzes the final step in the de novo biosynthesis of NAD+, an essential coenzyme for energy production, DNA repair, and cell signaling.

Loss-of-function variants in NADSYN1 impair NAD+ synthesis and are associated with severe congenital malformations and emerging links to broader metabolic and neurodevelopmental disorders.

What is NADSYN1 (NAD Synthetase 1)?

The NADSYN1 gene encodes NAD synthetase 1, a 706-amino-acid enzyme responsible for the final step in NAD+ (nicotinamide adenine dinucleotide) biosynthesis. This gene is located on chromosome 11q13.4 and primarily functions in the cytosol.

This enzyme functions as a homohexamer and includes key structural domains: a glutaminase domain, an NAD synthetase domain, and an ATP-binding motif. It utilizes glutamine or ammonia as an amide donor.

Role in NAD+ Biosynthesis (De Novo Pathway)

NADSYN1 catalyzes the final step of the de novo NAD+ biosynthetic pathway, converting nicotinic acid adenine dinucleotide (NaAD+) to NAD+ in an ATP-dependent reaction. This pathway uses tryptophan as a starting material, distinct from the salvage pathway that recycles nicotinamide.

Importance of NAD+ in Cellular Metabolism

NAD+ is essential for:

• Cellular energy production (glycolysis, TCA cycle, oxidative phosphorylation)
• DNA repair (PARP enzymes)
• Cell signaling (sirtuins, calcium channels)
• Gene expression and epigenetic regulation

When is NADSYN1 Testing or Research Relevant?

NADSYN1 testing may be relevant in the following scenarios:

Research on Metabolic Disorders and Related Conditions

NADSYN1 is increasingly studied in relation to:

• Congenital NAD+ Deficiency Disorders: Mutations impair NAD+ synthesis, resulting in systemic developmental defects.
• Pellagra-like Syndromes: Some cases mimic niacin deficiency symptoms despite adequate dietary intake.
• Neurodevelopmental and Aging-Related Disorders: Emerging links exist between NAD+ metabolism, brain aging, and neurodegeneration.
• Cancer: Altered NAD+ metabolism may contribute to tumorigenesis.

Limited Current Clinical Testing

Direct NADSYN1 testing is not widely available but may be included in research studies or exome panels for congenital anomaly syndromes.

NADSYN1 Genetic Testing: Test Procedure and Interpretation

Testing for NADSYN1 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for NADSYN1 genetic testing are considered to be without mutations that can alter the activity of the NADSYN1 proteins.

What Do Altered Levels or Mutations in NADSYN1 Mean?

Loss-of-function mutations in NADSYN1 impair NAD+ production, disrupting multiple cellular processes. This can lead to energy metabolism imbalances, increased oxidative stress, and metabolic derailment.

Clinical Manifestations

Biallelic NADSYN1 mutations cause Vertebral, Cardiac, Renal, and Limb Defects Syndrome 3 (VCRL3), an autosomal recessive disorder with:

• Congenital vertebral and limb malformations
• Renal agenesis or hypoplasia
• Cardiac anomalies
• Perinatal lethality in severe cases

Other presentations may include gastrointestinal issues, skin lesions, muscle weakness, or neurodevelopmental delay.

Known Pathogenic Variants

• p.Ala573Thr: Severe enzymatic impairment, ~86% NAD+ reduction
• p.Val607fs, p.Cys245Ter, p.Tyr613Ter: Truncating variants

Context-Dependent Interpretation

The impact depends on variant type, zygosity, maternal nutrient status, and other genetic/environmental factors.

What Does the Absence of Studied NADSYN1 Variants Mean?

A negative result for known NADSYN1 mutations does not rule out NAD+ deficiency or congenital malformation syndromes. Other genes and pathways may be involved, including NAD+ salvage or Preiss–Handler pathways.

Limitations of Current Testing

Absence of known pathogenic variants should be interpreted cautiously. Additional testing (e.g., metabolomics or whole-exome sequencing) may help in unresolved cases with strong clinical suspicion.

Clinical Implications and Future Directions

• Diagnosis: NADSYN1 testing should be considered in neonates with congenital anomalies affecting the spine, heart, kidneys, and limbs, especially with a family history of autosomal recessive inheritance.
• Therapeutic Research: Maternal supplementation with nicotinamide (not nicotinic acid) may prevent embryonic lethality in model organisms.
• Management: Nicotinamide supplementation postnatally may help restore NAD+ levels and alleviate some symptoms.
• Research Tools: Antibodies, ELISA kits, CRISPR constructs, and animal models are available for functional studies.

Conclusion

NADSYN1 is a critical gene for NAD+ biosynthesis and normal embryonic development. Mutations in this gene can cause severe congenital syndromes, and its role in NAD+ metabolism makes it a target of interest for metabolic, developmental, and aging-related research. 

Early identification and nutritional intervention may offer therapeutic potential in specific contexts.

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