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Recent work has shown that X-chromosome inactivation is brought about by Xist mRNA, which coats the inactive X-chromosome. This paper presents a hypothesis on the function of this RNA. It is suggested that interspersed repetitive elements of the LINE type, in which the X-chromosome is particularly rich, act as booster elements to promote the spread of Xist mRNA. Contact with this RNA causes the LINE elements to be sensed as repeated elements by the cell’s system for repeat-induced gene silencing. This leads to the silencing of these elements and the intervening unique sequences by their conversion to heterochromatin.

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The most studied example of transmission ratio distortion (TRD) in mice is that of the t-complex. This is a variant region of Chromosome 17 which exists as a polymorphism in wild mice. Males heterozygous for a t-haplotype and a normal Chr 17 transmit the t-haplotype to >50% of their young, up to 99%. Homozygous males are sterile. The TRD produced by the t-complex is due to the action of three or more distorter genes (Tcd) on a responder gene (Tcr). t-Haplotypes are maintained intact by crossover suppression induced by four neighboring inversions, the Tcd and Tcr loci lying in different inversions. Sperm formation is normal in t/t males, but sperm function is impaired through gross defects in sperm motility. The responder gene has been identified as a fusion gene formed from a sperm motility kinase and a ribosomal S6 kinase. Three candidate distorter genes have also been identified as genes coding for dynein chains, and thus possibly involved in sperm flagellar function.

Summary 1. The review considers information from mammalian embryology relevant to X‐chromosome inactivation, and from X‐inactivation relevant to mammalian embryology. 2. Properties of the inactive‐X, by which it may be recognized are: sex chromatin, heteropycnosis, late replication and the absence of gene product. Each of these has advantages and disadvantages in particular circumstances. In some species the X carries constitutive heterochromatin, which must be distinguished from the facultative region. 3. The time of X‐chromosome inactivation can be estimated from the time of appearance of sex chromatin or late replication, or inferred from the appearance of heterozygotes for X‐linked genes or of experimental chimaeras. The estimated time varies with species, and in the mouse and rabbit is near the time of increase in RNA synthesis. 4. Whereas in eutherian mammals either the maternally or the paternally derived X may be inactivated in different cell lines, in marsupials the paternal X is always the inactive one. 5. During development various factors act to distort the patterns produced by random X‐inactivation. These factors include cell selection, transfer of gene product, and migration and mingling of cells. 6. There is no clear evidence that X‐chromosome inactivation is not complete. 7. In female germ cells both X‐chromosomes appear to be active. In male ones both X and Y appear inactive during most of spermatogenesis, although probably in early stages all X chromosomes present are active. 8. The active and inactive X‐chromosomes may be differentiated by presence or absence of some non‐histone protein or other polyanionic substance. 9. If the genes concerned in synthesis or attachment of this substance are on the X‐chromosome then the differentiation will be self‐maintaining. 10. The initiation of the differentiation requires either the attachment of different X‐chromosomes to different sites, or some interaction of X‐linked and autosomal genes, concerned in inducing or repressing activity. Some possible models are discussed.

The extracellular calcium-sensing receptor (CaSR) plays a pivotal role in the regulation of extracellular calcium such that abnormalities, which result in a loss or gain of function, lead to hypercalcemia or hypocalcemia, respectively, in patients. Mice carrying CaSR knockout alleles develop hypercalcemia that mimics the disorders observed in humans. To date, there is no mouse model for an activating CaSR mutation. Here, we describe such a mouse model, named Nuf, originally identified for having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal-dominant manner, and mapping studies located the locus to chromosome 16, in the vicinity of the CaSR gene (Mouse Genome Database symbol Gprc2a). DNA sequence analysis revealed the presence of a Gprc2a missense mutation, Leu723Gln. Transient expression of wild-type and mutant CaSRs in human embryonic kidney 293 cells demonstrated that the mutation resulted in a gain of function of the CaSR, which had a significantly lower EC 50. Thus, our results have identified a mouse model for an activating CaSR mutation, and the development of ectopic calcification and cataract formation, which tended to be milder in the heterozygote Nuf mice, indicates that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CaSR mutations is required.

Complementary DNA clones from the pink-eyed dilution (p) locus of mouse chromosome 7 were isolated from murine melanoma and melanocyte libraries. The transcript from this gene is missing or altered in six independent mutant alleles of the p locus, suggesting that disruption of this gene results in the hypopigmentation phenotype that defines mutant p alleles. Characterization of the human homolog revealed that it is localized to human chromosome 15 at q11.2-q12, a region associated with Prader-Willi and Angelman syndromes, suggesting that altered expression of this gene may be responsible for the hypopigmentation phenotype exhibited by certain individuals with these disorders.

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