Sally Dunwoodie

NAD Deficiency, Congenital Malformations and vitamin B3 Supplementation



Congenital malformations arise due to genetic and environmental factors and understanding the interplay between these in causing malformation might lead to preventative opportunities, in some cases. Thus, we are identifying genetic and environmental factor that disrupt embryogenesis in humans and mice. Recently we identified genes and a metabolic pathway that are required for normal development and showed that mutation disrupted human and mouse embryogenesis, causing complex birth defects involving the heart, vertebrae and kidneys.

In families with vertebral and cardiac defects we identified mutations in two genes: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU), encoding kynurenine pathway enzymes. Three patients carried homozygous loss-of-function mutations in HAAO or KYNU and one patient carried compound heterozygous mutations in KYNU. All four patients had vertebral, cardiac and renal defects, amongst others and recurrent miscarriage was a feature in two families. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan via the kynurenine pathway. NAD is also synthesized more directly from vitamin B3. The patients had reduced circulating NAD levels. Haao or Kynu null mouse embryos developed similar defects to the patients, due to NAD deficiency. In null mice NAD deficiency, malformations and miscarriage were prevented by niacin (vitamin B3) supplementation during gestation.


Sally Dunwoodie gained a PhD researching the genetics of muscle development, at the Children’s Medical Research Institute, University of Sydney. She undertook postdoctoral training in embryology with Rosa Beddington at the National Institute for Medical Research in London. There she identified numerous genes necessary for normal mammalian embryogenesis. At the Victor Chang Institute in Sydney, Sally applied her understanding of the Notch Signalling Pathway in mouse to identify genetic causes of congenital vertebral defects in humans. Currently, she is embracing genome sequencing to identify disease-causing mutations in hundreds of families with heart defects. She is also exploring the impact that environmental factors and gene-environment interaction have on mouse embryogenesis. Sally Dunwoodie heads the Embryology Laboratory and the Chain Reaction Program in Congenital Heart Disease Research at the Victor Chang Cardiac Research Institute in Sydney. She is a Professor in the Faculties of Medicine and Science at the University of New South Wales.