@article {115, title = {Whole-Exome Sequencing in Familial Parkinson Disease.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 Jan}, pages = {68-75}, abstract = {

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5\% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6\% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

}, keywords = {Adult, Aged, Cohort Studies, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Parkinsonian Disorders, Protein-Tyrosine Kinases, Sequence Analysis, DNA, Tenascin}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.3266}, author = {Farlow, Janice L and Robak, Laurie A and Hetrick, Kurt and Bowling, Kevin and Boerwinkle, Eric and Coban-Akdemir, Zeynep H and Gambin, Tomasz and Gibbs, Richard A and Gu, Shen and Jain, Preti and Jankovic, Joseph and Jhangiani, Shalini and Kaw, Kaveeta and Lai, Dongbing and Lin, Hai and Ling, Hua and Liu, Yunlong and Lupski, James R and Muzny, Donna and Porter, Paula and Pugh, Elizabeth and White, Janson and Doheny, Kimberly and Myers, Richard M and Shulman, Joshua M and Foroud, Tatiana} } @article {247, title = {A form of the metabolic syndrome associated with mutations in DYRK1B.}, journal = {N Engl J Med}, volume = {370}, year = {2014}, month = {2014 May 15}, pages = {1909-1919}, abstract = {

BACKGROUND: Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome.

METHODS: We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene.

RESULTS: A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family.

CONCLUSIONS: These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.).

}, keywords = {Coronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Female, Founder Effect, Genetic Linkage, Genetic Predisposition to Disease, Glucose-6-Phosphatase, Humans, Hypertension, Male, Metabolic Syndrome, Mutation, Obesity, Abdominal, Pedigree, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases}, issn = {1533-4406}, doi = {10.1056/NEJMoa1301824}, author = {Keramati, Ali R and Fathzadeh, Mohsen and Go, Gwang-Woong and Singh, Rajvir and Choi, Murim and Faramarzi, Saeed and Mane, Shrikant and Kasaei, Mohammad and Sarajzadeh-Fard, Kazem and Hwa, John and Kidd, Kenneth K and Babaee Bigi, Mohammad A and Malekzadeh, Reza and Hosseinian, Adallat and Babaei, Masoud and Lifton, Richard P and Mani, Arya} }