UnIGENe stemmed from the research efforts of Corino Andrade and Paula Coutinho on familial amyloid neuropathy (FAP) ATTRV30M and Machado-Joseph disease (MJD). We focus on mechanisms of neurodegeneration, using hereditary ataxias (including MJD), FAP ATTRV30M, Huntington disease (HD) and other neurological diseases as models.
Our research has been centred mainly on new genes and mutations in families, functional studies and genetic modifiers for dominant (SCA) and recessive ataxias (FRDA, AOA), spastic paraplegias (SPG), Huntington and HD-like diseases.
We used animal models (natural mutant or transgenic mice, and C. elegans) for Friedreich ataxia (FRDA), MJD(/SCA3) and SCA6, to look into disease mechanisms and function of normal and mutant proteins. Cell models were used to characterize ataxin-3 interactors and assess the role of protein processing and degradation systems in neurodegenerative disorders.
We are also involved in the identification of disease modifiers and the role of epigenetic alterations in HD, MJD and FAP ATTRV30M.
Another of our interests are founder effects, ancestral haplotypes and mutational origins in MJD, but also SCA2, SCA10 and DRPLA, as well as in FAP ATTRV30M.
We are also concerned with some complex diseases, as migraine and Parkinson’s. We studied familial aggregation and ascertained susceptibility genes for common migraine, which is closely linked and has overlapping features and mechanisms with familial hemiplegic migraine, episodic ataxia and SCA6; channelopathies are also an interesting research path for neurodegeneration.
(1) A national systematic population-based survey on hereditary ataxias and spastic paraplegias; (2) identification of new genes and mutations in SCA, AOA and SPG families; (3) genomic mechanisms resulting in large gene rearrangements; (4) methylation at the ATXN3 promoter as a modifier in MJD; (5) population stratification has an impact in finding genetic modifiers for Huntington disease; (6) genetic components in common migraine identified; (7) evidence for anticipation in FAP ATTRV30M; (8) a worldwide study of mutational origins of MJD showed two major ancestral haplotypes - Joseph and Machado lineages, dating about 7,000 and 1,500 years ago - the Joseph haplotype having an Asian origin and being present also in Australian aborigines; (9) the (ATTCT)n expansion in SCA10 is probably of Amerindian origin; (10) quite surprisingly, large normal (unstable) alleles at the HD locus are present in 6% of the general population.
Clinical research is developed at CGPP (Centre for Predictive and Preventive Genetics, IBMC), and feeds back the bench with new research questions.
We published over 200 publications in peer-reviewed journals; 28 PhD students successfully completed their theses.
How communication of genetic information within the family is addressed in genetic counselling: A systematic review of research evidence. European Journal of Human Genetics24(3):315-325, 2016. [Journal: Article] [CI: 24] [IF: 4,3]
DOI: 10.1038/ejhg.2015.174 SCOPUS: 84958109101. .
Bras J., Alonso I., Barbot C., Costa M.M., Darwent L., Orme T., Sequeiros J., Hardy J., Coutinho P., Guerreiro R.,
Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. American Journal of Human Genetics96(3):474-479, 2015. [Journal: Article] [CI: 61] [IF: 10,8]
DOI: 10.1016/j.ajhg.2015.01.005 SCOPUS: 84924246336. .
Ramos E.M., Gillis T., Mysore J.S., Lee J.M., Gögele M., D'Elia Y., Pichler I., Sequeiros J., Pramstaller P.P., Gusella J.F., Macdonald M.E., Alonso I.,
Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease. American Journal of Medical Genetics - Neuropsychiatric Genetics168(2):135-143, 2015. [Journal: Article] [CI: 3] [IF: 3,4]
DOI: 10.1002/ajmg.b.32289 SCOPUS: 84923108709. .
da Conceição Pereira M., Morais S., Sequeiros J., Alonso I.,
Large-scale functional RNAi Screen in C. elegans identifies TGF-ß and notch signaling pathways as modifiers of CACNAIA. ASN Neuro8(2):, 2016. [Journal: Article] [CI: 5] [IF: 3]
DOI: 10.1177/1759091416637025 SCOPUS: 84961625995. .
Alves-Ferreira M., Coelho T., Santos D., Sequeiros J., Alonso I., Sousa A., Lemos C.,
A Trans-acting Factor May Modify Age at Onset in Familial Amyloid Polyneuropathy ATTRV30M in Portugal. Molecular Neurobiology55(5):3676-3683, 2018. [Journal: Article] [CI: 5] [IF: 4,6]
DOI: 10.1007/s12035-017-0593-4 SCOPUS: 85019539928. .
Paneque M., Sequeiros J., Skirton H.,
Quality issues concerning genetic counselling for presymptomatic testing: A European Delphi study. European Journal of Human Genetics23(11):1468-1472, 2015. [Journal: Article] [CI: 6] [IF: 4,6]
DOI: 10.1038/ejhg.2015.23 SCOPUS: 84944353845. .
Raposo M., Ramos A., Bettencourt C., Lima M.,
Replicating studies of genetic modifiers in spinocerebellar ataxia type 3: Can homogeneous cohorts aid?. Brain138(12):e398, 2015. [Journal: Letter] [CI: 13] [IF: 10,1]
DOI: 10.1093/brain/awv206 SCOPUS: 84951098086. .
Lemos C., Coelho T., Alves-Ferreira M., Martins-Da-Silva A., Sequeiros J., Mendonça D., Sousa A.,
Overcoming artefact: Anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M. Journal of Neurology Neurosurgery and Psychiatry85(3):326-330, 2014. [Journal: Article] [CI: 33] [IF: 6,8]
DOI: 10.1136/jnnp-2013-305383 SCOPUS: 84896709791. .
Quintas M., Neto J.L., Pereira-Monteiro J., Barros J., Sequeiros J., Sousa A., Alonso I., Lemos C.,
Interaction between γ-Aminobutyric Acid A Receptor Genes: New Evidence in Migraine Susceptibility. PLoS ONE8(9):, 2013. [Journal: Article] [CI: 10] [IF: 3,5]
DOI: 10.1371/journal.pone.0074087 SCOPUS: 84883511876. .
Coutinho P., Ruano L., Loureiro J.L., Cruz V.T., Barros J., Tuna A., Barbot C., Guimarães J., Alonso I., Silveira I., Sequeiros J., Neves J.M., Serrano P., Silva M.C.,
Hereditary ataxia and spastic paraplegia in Portugal: A population-based prevalence study. JAMA Neurology70(6):746-755, 2013. [Journal: Article] [CI: 55] [IF: 7]
DOI: 10.1001/jamaneurol.2013.1707 SCOPUS: 84878770734. .