A person's sex is determined by their complement of X and Y (sex) chromosomes. Someone who has two X chromosomes is genetically female and usually has ovaries and female external sex organs. Someone who has an X and a Y chromosome is genetically male and has testes and male external sex organs. Sometimes, though, the development of the reproductive organs proceeds abnormally, resulting in a person with an "intersex" condition whose chromosomes, gonads (ovaries or testes), and external sex organs do not correspond. Leydig cell hypoplasia (LCH; also called male pseudohermaphroditism or a disorder of sex development) is an XY female intersex condition. People with this inherited condition develop testes but also have a vagina (which is not connected to a womb), and they do not develop breasts or have periods. This mixture of sexual characteristics arises because the Leydig cells in the testes are underdeveloped. Leydig cells normally secrete testosterone, the hormone that promotes the development and maintenance of male sex characteristics. Before birth, chorionic gonadotropin (CG; a hormone made by the placenta) stimulates Leydig cell development and testosterone production; after birth, luteinizing hormone (LH), which is made by the pituitary gland, stimulates testosterone production. Both hormones bind to the LH/CG receptor, a protein on the surface of Leydig cells. In LCH, this receptor either does not bind CG and LH or fails to tell the Leydig cells to make testosterone.
These findings identify a new, functional exon in the LHCGR gene and show that mutations in this exon cause some cases of LCH. This is the first time that a human disease has been associated with mutations in an exon that is a target for NMD. In addition, these findings provide important insights into how the LHCGR is regulated. The researchers speculate that a complex network that involves the exon 6A-containing transcripts and NMD normally tightly regulates the production of functional LHCGR already at the transcriptional level. When mutations are present in exon 6A, they suggest, NMD is the predominant pathway for all the exon 6A-containing transcripts, thereby drastically decreasing the amount of functional LHCGR.
Most sensory systems follow the rule "one receptor molecule per receptor cell." For example, photoreceptors in the fly eye and cones in the human eye each express only one light-sensitive rhodopsin. Rhodopsins are G-coupled protein receptors, a class of ancient signaling molecules that mediate not just vision but also the sense of smell, the inflammatory response, and other physiological processes. However, the mechanisms that regulate mutual exclusion of receptor genes in the visual and olfactory systems are poorly understood. Each ommatidium in the fly eye consists of eight photoreceptors (R1-R8); six of which mediate broad-spectrum motion vision (R1-R6) and two that mediate color vision (R7 and R8). We identified a new class of photoreceptors in the fly retina that violates the one rhodopsin-one receptor rule. This subset of ommatidia, located in the dorsal third of the eye, co-expresses two ultraviolet-sensitive rhodospins (rh3 and rh4) in R7, while maintaining discrimination between green and blue opsins in R8. We took advantage of the genetic tools offered by the fruit fly to show that this co-expression depends on the Iroquois Complex (Iro-C) genes that are both necessary and sufficient to allow the two ultraviolet-sensitive rhosopsins to be expressed in the same R7 cell. These results shed new light on the mechanisms regulating co-expression of rhodopsins in the eye, and may well have implications for regulating co-expression in olfactory receptors and other G-protein coupled systems.