The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Noggin proteins are multifunctional extracellular regulators of cell signalling

Noggin is an extracellular cysteine knot protein that plays a crucial role in vertebrate dorsoventral (DV) patterning. Noggin binds and inhibits the activity of bone morphogenetic proteins (BMPs) via a conserved N-terminal Clip domain. Non-canonical orthologs of Noggin that lack a Clip domain (“Noggin-like” proteins) are encoded in many arthropod genomes are thought to have evolved into receptor tyrosine kinase (RTK) ligands that promote Torso/RTK signalling rather than inhibiting BMP signalling. Here, we examined the molecular function of noggin/noggin-like genes (ApNL1 and ApNL2) from the arthropod pea aphid using the dorso-ventral patterning of Xenopus and the terminal patterning system Drosophila to identify whether these proteins function as BMP or RTK signalling regulators. Our findings reveal that ApNL1 from the pea aphid can regulate both BMP and RTK signalling pathways, and unexpectedly, that the Clip domain is not essential for its antagonism of BMP signalling. Our findings indicate that ancestral noggin/noggin-like genes were multifunctional regulators of signalling that have specialised to regulate multiple cell signalling pathways during the evolution of animals