Molecular genetics of mineral metabolic disorders

Abstract

The recent advances in molecular biology and cytogenetics have made it possible to localize, clone and characterize some of the genetic abnormalities which result in disorders of phosphate and calcium homeostasis. Thus, the genes causing X-linked hypophosphataemic rickets, Lowe syndrome, X-linked recessive hypoparathyroidism, Di George syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and vitamin D-dependent rickets type I have been mapped. In addition the genes involved in the pathogenesis of the humoral hypercalcaemia of malignancy, vitamin D-dependent rickets type II, pseudohypoparathyroidism, and some of the autosomal forms of hypoparathyroidism have been cloned and the mutations characterized. The molecular and genetic studies which have mapped and identified these disease genes are described and the implications of these developments in clinical practice and in further elucidation of the mineral metabolic defects are discussed.

Proximal Tubular Phosphate Reabsorption: Molecular Mechanisms

“…The genetic aspects of proximal tubular Na-P i cotransport have been covered in many reviews (e.g., Refs. 338,384,390), and we only mention those disorders that have been characterized at the molecular level. Several genetic defects resulting in isolated renal phosphate wasting have been described, such as X-linked hypophosphatemic rickets (XLH; e.g., Refs.…”

“…The first is caused by mutations in the PHEX gene, which has homology to neutral endopeptidase genes and is hypothesized to process or degrade a circulating factor that regulates by an unknown mechanism renal brush-border membrane Na-P i cotransport (see below; for review, see Refs. 110,112,384,390). A candidate gene for ADHR and/or HHRH could be the brush-border membrane Na-P i cotransporter (see below).…”

“…Other genetic defects in renal P i handling are secondary to changes in vitamin D, PTH, or acid/base metabolism or are a consequence of more general metabolic disorders (for review, see Refs. 109,216,217,338,390).…”

Central and autonomic nervous system links to the APUD system (and their APUDomas)

“…The locus for MEN-I is on the short arm of chromosome 11. The genetics of MEN-2 tumours are more complex with deletions occurring on chromosome 10 and 1 [8]. Of note, gliomas that are of neuroectodermal origin have shown fre-quent chromosome 10 abnormalities [9].…”