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TRENDS in Genetics Vol.18 No.4 April 2002
http://tig.trends.com 0168-9525/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
181News&Comment
Journal Club
In addition to sperm, the seminal fluid ofmale Drosophila contains about 80 proteinsthat are produced by the accessory glands.In the reproductive tracts of mated females,these accessory gland proteins (Acps)mediate sperm storage, stimulate theproduction and laying of eggs, anddecrease the female’s receptivity to furthermating. Acps also cause a dose-dependentincrease in female mortality. This negativeeffect on females is probably an unintendedbyproduct of the positive functions theseproteins have for males.
Lung et al. [1] have identified a particularprotein (Acp62F) that is toxic whenectopically expressed during pre-adultdevelopment in Drosophila melanogaster.Repeated overexpression of this proteinalso reduces the lifespan of adult femalesand, possibly, of adult males. Under normalcircumstances, this protein probably affectsfemales negatively, but not males. Thedifference is that, whereas in males, Acp62Fis found only in the reproductive tract, in
females about 10% of the protein escapesfrom the reproductive tract into thecirculating hemolymph. Although otherAcps could also have a negative effect onfemale fitness, it is unlikely that most do.None of the other seven Acps tested causeda significant negative effect whenexpressed ectopically.
What is the mechanism underlyingAcp62F toxicity? Lung et al. present severallines of evidence that point to it being aprotease inhibitor. A FASTA search forsimilar sequences returned a trypsininhibitor from the roundworm (Ascaris) as its top hit. Acp62F also shares manystructural features with a family of proteaseinhibitors that all possess five disulfidebridges. In addition, the researchersdetected in vitro protease inhibitor activityfrom Acp62F. One probable positivefunction of Acp62F is the protection ofsperm or perhaps other seminal fluidproteins from proteases. Protease inhibitorshave also been found in mammalian
seminal fluid, suggesting that this is acommon component of seminal fluids.
Pinpointing toxic effects to the ectopicexpression of a single protein opens thedoor to more questions. If Acp62F were tobe overexpressed in the male reproductivetract, would the seminal fluids of thosemales be more toxic? Does natural variationin Acp62F levels in male seminal fluidcorrespond to either offensive and/ordefensive ability in sperm competition?Does this variation correspond with themyriad effects seen in mated females? Thisstudy and previous ones also suggest anunderstanding of female resistance to Acpscould be facilitated by investigating howAcps enter the female hemolymph.
1 Lung, O. et al. (2002) The Drosophilamelanogaster seminal fluid Acp62F is aprotease inhibitor that is toxic upon ectopicexpression. Genetics 160, 211–224
Norman Johnson
Why is seminal fluid toxic?
In all branches of science, results thatappear anomalous or depart from the normforce us to rethink the rules and challengeaccepted dogma. The discovery that some genes are imprinted was one suchdeparture. Whereas in classical mendeliangenetics, the parental origin of a gene isunimportant, a small proportion of genesare imprinted with a ‘memory’ of whetherthey are maternally or paternally derived,and their transcription patterns are setaccordingly. These imprints are oftenuncovered by unusual patterns ofinheritance of genetic diseases.
The GNAS1 locus on humanchromosome 20 is already known to becomplex. At least three transcripts derivefrom various combinations of exons:NESP55 is maternally expressed, XLαs is paternally expressed, and Gsα isbiallelically expressed in most tissues, but imprinted in a few. Imprinting of thislocus was first indicated by the unusualinheritance observed in families withAlbright hereditary osteodystrophy (AHO),a condition characterized by short stature,
developmental delay, obesity andmetaphalangeal shortening. Some AHO patients also showpseudohypoparathyroidism type 1A(PHP1A), a resistance to the effects ofseveral hormones, particularly parathyroidhormone and thyroid-stimulating hormone.PHP1A almost always results frommaternally inherited mutations of Gsα;paternal transmission of the same mutationin the same family causes AHO withouthormone resistance. This could beexplained if Gsα is imprinted in the targetsites for these hormones; for instance, the thyroid and renal tubule.
A study by Shore and colleagues [1] nowshows that even this view is simplistic.First, they demonstrate that mutations of Gsα can give rise to a very differentcondition, progressive osseousheteroplasia (POH), in which extensiveinappropriate bone formation in soft tissuecauses progressive disability. In somecases, the POH mutations were identical to those already described in families withAHO. Where the parental origin could be
determined, the mutations were allpaternally derived. Two transmittingfathers were not clinically affectedthemselves. Most intriguingly, in onefamily where three females with POHpassed the mutation on, their children wereaffected by AHO, not POH. The hormonestatus of these children is not mentioned,so it is unclear whether they have PHP1A.
So why do paternally inherited Gsαmutations lead to AHO in some families and POH in others? Existing models ofimprinting cannot fully explain theseobservations, and further analysis ofpotential genetic and epigenetic modifiersis required. This complex locus and itsassociated genetic disorders have yet moreinteresting biological secrets to yield.
1 Shore, E. M. et al. (2002) Paternally inheritedinactivating mutations of the GNAS1 gene inprogressive osseous heteroplasia. New Engl. J.Med. 346, 99–106
Micheala Aldred
GNAS1 imprinting: the latest twist
