Single gene variants in risk and protection: a new view on the genetic etiology of Parkinson’s disease

Most of the research into the cause of Lewy disorders has focused on Parkinson’s disease, since that is the best defined of these conditions and, therefore, the most straightforward to study. Dementia with Lewy bodies (DLB) is more difficult to diagnose with certainty, especially in the early years of the disease. What we collectively learn about Parkinson’s disease will likely be very relevant to our understanding of DLB. Multiple investigations have linked Parkinson’s disease to both environmental exposures and genetic factors. However, these associations have all been modest, and none of them accounts for more than a few percent of the contribution to the cause of sporadic Parkinson’s disease (i.e., the attributable risks are low). These investigations are ongoing and hopefully will soon provide a more complete understanding of the cause(s). Perhaps the most important clue to all Lewy conditions is located in the brain: the Lewy body itself. A recent sophisticated analysis of Lewy bodies revealed approximately 300 different component proteins. However, we already knew that Lewy bodies contain high concentrations of a normal protein called alpha synuclein. In fact, Lewy bodies are conventionally identified under the microscope with antibody stains that specifically bind to alpha synuclein. Could this be the crucial protein among the nearly 300? While the alpha synuclein story is focused on Parkinson’s disease, it may be just as relevant to DLB, as we shall see. The story starts with a large Italian-American family with Parkinson’s disease, studied by Dr. Lawrence Golbe and colleagues at the Robert Wood Johnson Medical Center in New Brunswick, New Jersey. In this rare family, many members of multiple generations had been affected by Parkinson’s disease (with Lewy bodies), consistent with a single gene passed on with dominant inheritance. It took a number of years to identify that abnormal gene, which ultimately was proven to be the gene coding for alpha synuclein. It was quickly discovered that this genetic error is not present in usual cases of Parkinson’s disease.

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Extended Study of NUS1 Gene Variants in Parkinson's Disease

Frontiers in Neurology ◽

10.3389/fneur.2020.583182 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lamei Yuan ◽

Xiangyu Chen ◽

Zhi Song ◽

Weidong Le ◽

Wen Zheng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gene Variants ◽

Extended Study

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High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-02288 ◽

2019 ◽

Vol 104 (10) ◽

pp. 4273-4281 ◽

Cited By ~ 8

Author(s):

Lukas Plachy ◽

Veronika Strakova ◽

Lenka Elblova ◽

Barbora Obermannova ◽

Stanislava Kolouskova ◽

...

Keyword(s):

Short Stature ◽

Growth Plate ◽

Single Gene ◽

Gene Variants ◽

Genetic Etiology ◽

Associated Proteins ◽

Genetic Mechanisms ◽

Standards And Guidelines ◽

Minimum Height ◽

Severe Short Stature

AbstractContextFamilial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date.ObjectivesTo identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD).Design, Settings, and PatientsOf 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height −2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines.ResultsIn 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1).ConclusionsSingle-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.

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