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NAD+ Deficiency Mutations Organ Malformations

An image showing DNA

Congenital NAD Deficiency Disorder (CNDD) is a syndrome in which DNA abnormalities result in inadequate quantities of NAD+, an important component for all cells. During development, these patients have abnormalities of the heart, kidney, vertebrae, and limbs.

Researchers uncovered new mutations connected to CNDD. These mutations affect three genes involved in NAD+ production, causing moderate to severe NAD shortage in yeast, as well as in humans. The findings assist in identifying altered enzymatic stages in the NAD+ production pathway, which may improve future treatment development.

All animals, including humans, generate and utilize NAD+ during pregnancy, an important cofactor involved in over 400 physiological processes. The kynurenine pathway uses dietary L-tryptophan to produce NAD+. Mutations in three genes — KYNU, HAAO, and NADSYN1 — encoding kynurenine pathway enzymes alter NAD+ synthesis and occur in individuals with heart, kidney, vertebral, and limb abnormalities. These CNDD patients have various DNA mutations that may impact development. However, the mutations that cause CNDD remain unknown.

A Study Identifies Novel NAD+ Biosynthesis Enzyme Mutations

This study examined the mutations in 7 patients from different families who had developmental defects consistent with CNDD to gain a better understanding of the relationship between DNA mutations that disrupt NAD+ synthesis and abnormal human development. They discovered unique mutations in two genes encoding kynurenine pathway enzymes — 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) and kynureninase (KYNU).

Three individuals had mutations in the HAAO enzyme, which is involved in the synthesis of NAD+ from the amino acid L-tryptophan. All three individuals with HAAO had abnormalities consistent with those previously described: heart, vertebrae, limbs, and kidney anomalies.

Researchers also looked at four individuals who had mutations in the gene encoding the enzyme kynureninase (KYNU), which is similarly involved in the synthesis of NAD+ from tryptophan. These people had limb deformities, cardiac abnormalities, and changed facial characteristics such as widely spread eyes, a short neck, and a large nose — all of which were characteristic of CNDD.

Not Every Mutation Is Equal

To determine whether these mutations had an effect on NAD+ synthesis, the study team implanted the mutations into yeast, which has the same enzymes involved in the NAD+ production pathway as humans. Dunwoodie and colleagues determined whether these mutations influence NAD+ synthesis in humans by tracking the development and NAD+ production of this yeast. When they cultivated yeast with these mutations in HAAO, they saw that the single-celled organisms developed at a substantially slower rate and had lower total NAD+ levels. Similarly, when they injected these patients’ KYNU mutations into yeast, they saw decreases of at least 57% of NAD+ in comparison to healthy, non-mutated yeast.

Currently, all HAAO or KYNU mutations associated with Congenital NAD Deficiency Disorder result in the total loss of function of these enzymes. The Australian research team detected many unusual and detrimental mutations in HAAO or KYNU that cause moderate to total loss of function and NAD shortage. Generally, the more severe these mutations impair NAD production in yeast, the more abnormalities are detected in affected humans.

Vitamin B3 Supplementation May Help Prevent Miscarriage

This work contributes to our knowledge of CNDD by establishing that uncommon, harmful mutations within HAAO or KYNU might induce deformity owing to diminished enzyme activity. This shows that NAD deficiency can be caused by a mix of common and less harmful gene changes. However, the study suggested that supplementing mothers’ NAD+ levels with vitamin B3 precursors during pregnancy may help prevent newborns from developing abnormally due to NAD+ shortage.

Additionally, the study demonstrated that the CNDD produced by these newly discovered mutations is caused by the loss of function of critical NAD+ production enzymes. Researchers can then utilize this information to design treatment strategies that restore these enzymes’ function.