The Genetics and Development of Scoliosis by Kenro Kusumi & Sally L. Dunwoodie

Author:Kenro Kusumi & Sally L. Dunwoodie
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Congenital NAD Deficiency Disorders

Recently, nicotinamide adenine dinucleotide (NAD) deficiency was robustly reported in a group of patients with multiple congenital malformations similar to VACTERL. Before this report, many causes of isolated organ defects had been identified, such as heart defects and vertebral malformation. But the genetic causes of isolated cardiac or vertebral defects appear to have little relevance when these defects occur in combination. In the study, Shi et al. [77] enrolled patients with congenital vertebral and heart malformations from four families. Whole exome/genome sequence identified biallelic pathogenic HAAO and KYNU variants in these patients. In vitro assay proved that loss of HAAO or KYNU activity leads to increased plasma levels of metabolites upstream of these enzymes and reduced levels downstream, including NAD. Homozygous null mutant mice showed that all the Haao −/− and Kynu −/− embryos had multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis, recapitulating the human phenotype. Importantly, these mice could be rescued by niacin (vitamin B3) supplementation, indicating that loss of embryonic NAD leads to embryo defects and death. The rescue experiment also indicates that vitamin B3 supplementation might prevent miscarriage and malformation in humans.

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