Could you explain, in layman's terms, what happens genetically when a father, daughter, and male child of the daughter all have DI?

Topic: NDI: An Overview
Author: Wildin, Robert
There are many forms of DI: nephrogenic DI, neurogenic DI and primary polydipsia. Neurogenic DI is caused when the hypothalamus does not produce or secrete the antidiuretic hormone, arginine vasopressin (AVP). Primary polydipsia, a chronic intake of excessive volumes of water, remains a mystery as to its causes, which are often attributed to some type of psychological imbalance.

However, if the type of DI you are talking about is nephrogenic DI (nephrogenic diabetes insipidus or NDI), and specifically the molecular basis of inherited NDI, then researchers have to date found two genes, either of which, when mutated, can cause NDI. By far, the most common cause of inherited NDI is a mutation of the vasopressin-2 receptor (V2R) gene. This form of NDI is called X-linked NDI because the V2R gene is carried on the X chromosome.

The V2R is a receptor protein that the hormone AVP must bind with in order to start the molecular sequence which allows the kidneys to reabsorb most of the body water that flows through them and to concentrate urine. This is how the kidneys maintain body water balance.

When the V2R is defective due to a mutated AVPR2 gene, (the AVPR2 gene makes the V2R) AVP cannot bind with it, and NDI results. The V2R gene is carried on the X chromosome. The X chromosome is known as the female sex chromosome, as females have two, and males have only one. Females, then, have a V2R gene on each of their X chromosomes, so they have a pair of V2R genes. If one of those V2R genes is mutated, they have another V2R gene on their other X chromosome that may not be mutated. V2R gene mutations are recessive, which means both the V2R genes a person inherits would have to be mutated in order for NDI to express its symptoms: chronic, excessive urination and thirst.

Males only have one X chromosome, which they inherit from their mother. So if the mother had a mutated V2R gene on one of her chromosomes, and that is the chromosome her son inherits from her, then he will express the symptoms of NDI because he has not inherited any other X chromosome that might carry a normal V2R gene. That is why, in X-linked NDI, the general inheritance pattern is this: females can carry the mutated V2R gene and pass it on to their sons who will express NDI. The sons, in turn, will pass on the gene to all of their daughters and none of their sons.

Females who carry the mutated V2R gene can express the symptoms of NDI to varying degrees but rarely as severely as do their sons. The reason they can express lighter symptoms is because the normal V2R gene may not be able to completely compensate for the mutated one. All of a female's X chromosomes in the cells in excess of one are inactivated by some unknown process called X-inactivation. In some cells, the X chromosome with the NDI gene is inactivated. These cells are normal. In other cells, the X chromosome with the normal gene is inactivated. Since the NDI X chromosome remains active, and is the only active X, these cells are just like the ones in boys with NDI. Most carrier females have little to no symptoms because having half of their cells expressing the normal X chromosome is sufficient. But some females are unlucky and have, by random chance, any fewer than half of their cells expressing the normal X. These women have varying degrees of symptoms.

The other gene that, when mutated, causes NDI is the gene that produces aquaporin-2 (AQP2), a water-transporting protein that helps the kidney reabsorb water and concentrate urine. The AQP2 gene is carried on a non-sex chromosome (chromosome 12), so that it is carried by both males and females. A baby will inherit one AQP2 gene from his or her mother, and one from the father. A mutated AQP2 gene is recessive; that is, if only one of a person's AQP2 gene pair is mutated, that person will not express the symptoms of NDI. However, if the baby inherits a mutated AQP2 gene from both mother and father, then both of the baby's AQP2 gene pairs are mutated and the baby will express the symptoms of NDI.

The most likely explanation is that the father had X-linked NDI. He passed the gene on to his daughter, who had symptoms because more of her cells expressed the NDI X chromosome than the normal one. She passed on her NDI X chromosome to her son, who has NDI.

Alternatively, the family could have neurogenic (central) NDI, which is sometimes passed through families without regard to sex.