Discovering genetic causes of
zinc deficiency has been a remarkable scientific journey. It started with the description of a rare
skin disease, its treatment with various agents, the successful therapy with
zinc, and the identification of mutations in a
zinc transporter causing the disease. The journey continues with defining the molecular and cellular pathways that lead to the symptoms caused by
zinc deficiency. Remarkably, at least two
zinc transporters from separate
protein families are now known to be involved in the genetics of
zinc deficiency. One is ZIP4, which is involved in intestinal
zinc uptake. Its mutations can cause
acrodermatitis enteropathica (AE) with autosomal recessive inheritance. The other one is ZnT2, the transporter responsible for supplying human milk with
zinc. Mutations in this transporter cause transient neonatal
zinc deficiency (TNZD) with symptoms similar to AE but with autosomal dominant inheritance. The two diseases can be distinguished in affected infants. AE is fatal if
zinc is not supplied to the infant after weaning, whereas TNZD is a genetic defect of the mother limiting the supply of
zinc in the milk, and therefore the infant usually will obtain enough
zinc once weaned. Although these diseases are relatively rare, the full functional consequences of the numerous mutations in ZIP4 and ZnT2 and their interactions with dietary
zinc are not known. In particular, it remains unexplored whether some mutations cause milder disease phenotypes or increase the risk for other diseases if dietary
zinc requirements are not met or exceeded. Thus, it is not known whether widespread
zinc deficiency in human populations is based primarily on a
nutritional deficiency or determined by genetic factors as well. This consideration becomes even more significant with regard to mutations in the other 22 human
zinc transporters, where associations with a range of diseases, including diabetes,
heart disease, and
mental illnesses have been observed. Therefore, clinical tests for
genetic disorders of
zinc metabolism need to be developed.