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Researchers are getting closer toidentifying MYAS1, a locus in thehuman HLA complex associated withsusceptibility to acquired generalisedmyasthenia gravis, an autoimmuneneurological disorder. Henri-JeanGarchon (Institut National de la Santéet de la Recherche Médicale U580,Paris, France) and colleagues reportthat MYAS1 maps to the class IIIregion of the HLA complex, a regionthat contains genes involved in theformation of germinal centres, struc-tures that actively produce antibodies.

Myasthenia gravis is characterisedby skeletal muscle weakness thatincreases after exercise. Respiratorymuscles can also be affected, leading torespiratory failure in the most severecases. Most patients with myastheniagravis produce high titres of antibodiesto the acetycholine receptor present atneuromuscular junctions. Theseantibodies impair the transmission ofnerve impulses to the muscles.

The commonest form ofmyasthenia gravis, says Garchon,“affects young women and ischaracterised by an anomaly of thethymus called follicular hyperplasia.The thymus of these patientseffectively turns into a kind of lymphnode producing autoantibodies.”

By measuring the association of 27marker genes in the HLA region withmyasthenia gravis in 73 families with asingle case of this common form of thedisorder, Garchon and his team havelocalised MYAS1 to a 1·2 Mbp genomesegment. They also identify a corehaplotype (a set of alleles that isinherited as a block) that is stronglyassociated with this type of myastheniagravis and with higher titres ofantibodies against the acetylcholinereceptor (Proc Natl Acad Sci USA2004; 101: 15464–69).

“Our results clearly show that classIII HLA genes are involved in diseasedevelopment and not class II genes

[genes involved in the presentation ofantigens to lymphocytes] as previouslythought”, says Garchon. Possiblecandidate genes for MYAS1 in theregion, Garchon notes, include the lymphotoxin genes, which areinvolved in germinal centre formation.

“This is a [thought] provokingpaper that suggests the possibleinvolvement of immune responsegenes other than HLA I or II, inmyasthenia gravis in youngerpatients”, comment Nick Willcox andAngela Vincent (Institute of MolecularMedicine, Oxford, UK). “The resultssuggest that polymorphic variants ofmolecules such as lymphotoxin could,for instance, influence the formationof germinal centres and lead to higherantibody titres.” Further work is nowrequired to explain why patientsdevelop the immune response in thefirst place, note both the Oxfordresearchers and Garchon.Jane Bradbury

Homing in on myasthenia-gravis gene

Neurology Vol 3 December 2004 http://neurology.thelancet.com

Drosophila model increases understanding of fragile-X syndrome

Fragile-X syndrome, the mostcommon form of inherited mentalretardation, is caused by a mutationin the FMR1 gene, which encodesFMRP, an RNA-binding translationregulator. What we have found isthat fragile X negatively regulatesneuronal structural complexity, saidstudy author Kendal Broadie(Vanderbilt University, Nashville,TN, USA). “This misregulation existsthroughout the neuron, and it leadsto incorrect neural circuit contactand impaired synaptic terminaldifferentiation. In the patient, thismeans increased process formationand growth.”

In a Drosophila model of fragile-Xsyndrome, Broadie and colleaguesinvestigated the role of DrosophilaFMRP (dFMRP) in the central brain.The researchers concentrated on themushroom body, the insect brain’slearning and memory centre, which isthought to be analgous to thehippocampus. In mushroom-bodyneurons, dFMRP bidirectionally

regulates several levels of structuralarchitecture, including processformation from the soma, dendriticelaboration, axonal branching, andsynaptogenesis. Analysis of thestructure of Drosophila-fmr1-nullmutant neurons revealed enlargedsynaptic boutons, irregular boutonsize, and abnormal accumulation ofsynaptic vesicles. These defectsindicate the impairment of normalsynaptogenesis, and suggest arrestedsynaptic function (Curr Biol 2004; 14:1863–70).

Results from a Drosophila modelare applicable to the humansyndrome, explained Broadie. “It isnow extremely well established thatDrosophila neurons are patterned andfunction through very highlyconserved molecular and cellularpathways. Indeed, our previous workon fragile-X syndrome indicatedimpaired regulation of thetranslational control of microtubule-associated-protein 1B, leading tohyperstabilised microtubules and

neuronal patterning defects. All of thiswork has just recently been retestedand confirmed exactly in the mousemodel (Proc Natl Acad Sci USA 2004;101: 15201–06).”

The results are very convincingand the quality of figures is superb,commented Rob Willemsen (ErasmusMC, Rotterdam, the Netherlands).“However, the results confirm earlierstudies in Fmr1 knockout mice andDrosophila and do not show excitingnew data that changes our view aboutcellular FMRP function.”

“In addition, we have to realisethat in Drosophila melanogaster onlyone gene is present, said Willemsen,“whereas in mammals three genes arepresent. Thus, to extrapolate theresults obtained in Drosophila to thehuman situation we have to makesome reservations. Some of theaspects of dFMRP that we observe inDrosophila may be due to FXR1P orFXR2P function in mammals andmen.”Roxanne Nelson