Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Among these, Monoamine oxidase A (MAOA) catalyzes the degradation ...of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene have been associated with Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function, specifically in dopaminergic (DA) neurons. Here we generated human induced pluripotent stem cell (hiPSC)-derived DA neurons from three individuals with Brunner syndrome carrying different mutations and characterized neuronal properties at the single cell and neuronal network level in vitro. DA neurons of Brunner syndrome patients showed reduced synaptic density but exhibited hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected in DA neurons of individuals with Brunner syndrome. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), resulting in increased NMDAR-mediated currents. By correcting a MAOA missense mutation with CRISPR/Cas9 genome editing we normalized GRIN2A and GRIN2B expression, NMDAR function and neuronal population activity to control levels. Our data suggest that MAOA mutations in Brunner syndrome increase the activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to the etiology of Brunner syndrome associated phenotypes.
•Mutations in MAOA lead to increased dopaminergic neuron network activity.•Upregulated NMDAR function drives the MAOA mutation phenotype.•CRISPR-CAS9 mediated rescue reverses NMDAR and network activity to control levels.
Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental ...and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
Irreversible hearing loss is a frequent side effect of the chemotherapeutic agent cisplatin and shows considerable interpatient variability. The variant rs1872328 in the ACYP2 gene was recently ...identified as a risk factor for the development of cisplatin-induced ototoxicity in children with brain tumors. We aimed to replicate this finding in patients with osteosarcoma.
An independent cohort of 156 patients was genotyped for the rs1872328 variant and evaluated for the presence of cisplatin-induced ototoxicity.
A significant association was observed between carriership of the A allele and cisplatin-induced ototoxicity after the end of treatment (P=0.027).
This is the first study replicating the association of ACYP2 variant rs1872328 with cisplatin-induced ototoxicity in patients with osteosarcoma who did not receive potentially ototoxic cranial irradiation. Hence, the ACYP2 variant should be considered a predictive pharmacogenetic marker for hearing loss, which may be used to guide therapies for patients treated with cisplatin.
Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic ...variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate genetic variants as predictors for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10 genetic variants and evaluated for their association with cisplatin-induced ototoxicity (
,
,
and
) and nephrotoxicity (
,
and
). Ototoxicity was determined by patient-reported complaints as well as tone audiometrical assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance during treatment compared to baseline. A significant association was observed between carriership of the A allele for rs1872328 in the
gene and cisplatin-induced clinically determined ototoxicity (
= 0.019), and not for ototoxicity measured by tone audiometrical assessments (
= 0.449). Carriership of a T allele for rs316019 in the
gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (
= 0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients genetic variants in
are significantly associated with clinically determined ototoxicity. Validation studies are necessary to prove the added value for individualized treatments plans in these patients.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention and/or hyperactivity and impulsivity. ADHD is highly ...prevalent in childhood and often persists into adulthood. Both genetic variants and environmental factors play a role in the onset and persistence of ADHD, and epigenetic changes, such as DNA methylation are considered as a link for their interplay. To investigate this, we studied DNA methylation in 37 candidate genes by performing targeted bisulfite sequencing of DNA isolated from whole blood of N = 88 individuals diagnosed with adult ADHD and N = 91 unaffected individuals (mean age 34.2 years). Differentially methylated sites were assessed by generalized linear models testing ADHD status and ADHD symptoms, accounting for a methylation-based smoking score, age, sex, and blood cell count. DNA methylation of single sites within DRD4 and KLDR1 was associated with adult ADHD status, and multiple DNA methylation sites within TARBP1 were associated with ADHD symptoms in adulthood and childhood. Awaiting replication, findings of this pilot study point to TARBP1 as a new candidate gene for ADHD symptoms. Our work also stresses the need for research to further examine the effects of environmental factors, such as nicotine exposure, on epigenetic modifications associated with psychiatric traits.
•TARBP1 DNA methylation is associated with ADHD symptoms.•DNA methylation in DRD4 and KLDR1 is associated with persistent ADHD status.•Targeted bisulfite sequencing provides broader coverage of 37 ADHD candidate genes.•Association of prenatal smoking exposure with DNA methylation differences of TARBP1.•DNA methylation levels in TARBP1 as possible link between environment and ADHD.
Aims
Studies implicated a role for a genetic variant in CEP72 in vincristine‐induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumour patients, to ...perform a cross‐disease meta‐analysis and explore the protein‐coding region of CEP72.
Methods
In total, 104 vincristine‐treated brain tumour patients were genotyped for CEP72 rs924607, and sequenced for the protein‐coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta‐analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72.
Results
Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (odds ratio, OR 95% confidence interval, CI 2.076 0.359–11.989, P = .414). When combined with 8 cohorts (1095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR 95% CI 2.15 1.35–3.43, P = .001). Additionally, a missense variant (rs12522955) was significantly associated (OR 95% CI 2.3 1.2–4.4, P = .041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (P = .039).
Conclusion
The association of CEP72 rs924607 in vincristine‐induced neuropathy was not confirmed in a cohort of brain tumour patients, but did contribute to its suggested effect when combined in a cross‐disease meta‐analysis. The importance of other genetic variations in CEP72 on vincristine‐induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine‐induced toxicity, and provides guidance for future prospective studies.
Abstract Parkinson's disease (PD) is a neurodegenerative disorder caused by nigrostriatal dopaminergic degeneration. Brain-derived neurotrophic factor (BDNF) is a key protein in brain plasticity and ...is particularly important for survival of dopaminergic neurons. The Val66Met polymorphism of BDNF (rs6265) has been associated with functional differences (mainly cognitive) between healthy adults and also with differences in the clinical expression of several other neuropsychiatric illnesses including PD. However, these studies used different outcome measures, have not been replicated, and were cross sectional, making it difficult to establish the role of BDNF in the clinical variability of PD. Here, a large cohort of 384 PD patients were followed up for 2 years, and associations between BDNF genotype and various clinical characteristics were examined. The BDNF Met-allele carriers showed a significantly smaller decline in set shifting during follow-up compared with the homozygous BDNF Val-allele carriers. Contrary to previous assumptions, these results indicate that mental flexibility is one of the cognitive processes that may benefit from the BDNF Met allele in PD patients.
Background
The nitric oxide synthase gene (
NOS
1)
exon 1f (ex1f)
VNTR
is a known genetic risk factor for Attention‐Deficit/Hyperactivity Disorder (
ADHD
), particularly in females.
NOS
1
plays an ...important role in neurite outgrowth and may thus influence brain development, specifically white matter (
WM
) microstructure, which is known to be altered in
ADHD
. The current study aimed to investigate whether
NOS
1
is associated with
WM
microstructure in (female) individuals with and without
ADHD
.
Methods
Diffusion Tensor Imaging (
DTI
) scans were collected from 187 participants with
ADHD
(33% female) and 103 controls (50% female), aged 8–26 years, and
NOS
1
‐ex1f
VNTR
genotype was determined. Whole‐brain analyses were conducted for fractional anisotropy (
FA
) and mean diffusivity (
MD
) to examine associations between
NOS
1
and
WM
microstructure, including possible interactions with gender and diagnosis.
Results
Consistent with previous literature,
NOS
1
‐ex1f was associated with total
ADHD
and hyperactivity‐impulsivity symptoms, but not inattention; this effect was independent of gender.
NOS
1
‐ex1f was also associated with
MD
values in several major
WM
tracts in females, but not males. In females, homozygosity for the short allele was linked to higher
MD
values than carriership of the long allele.
MD
values in these regions did not correlate with
ADHD
symptoms. Results were similar for participants with and without
ADHD
.
Conclusions
NOS
1
‐ex1f
VNTR
is associated with
WM
microstructure in females in a large sample of participants with
ADHD
and healthy controls. Whether this association is part of a neurodevelopmental pathway from
NOS
1
to
ADHD
symptoms should be further investigated in future studies.
Background
The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention‐Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an ...important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD.
Methods
Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8–26 years, and NOS1‐ex1f VNTR genotype was determined. Whole‐brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis.
Results
Consistent with previous literature, NOS1‐ex1f was associated with total ADHD and hyperactivity‐impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1‐ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD.
Conclusions
NOS1‐ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.
PDF
