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Applications of imaging genomics beyond oncology
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Xiaohui Yao, Jingwen Yan, Li Shen
As with many other complex diseases, a substantial progress in the discovery of genetic factors contributing to the pathology of bipolar disease has been achieved by genome-wide association studies. Testing 1.8 million variants in 4,387 cases and 6,209 controls, Ferreira et al. identified the region of ankyrin 3 (ANK3) and calcium voltage-gated channel subunit alpha1 C (CACNA1C) in strong association with disease risk [138]. The Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) later reported results with an even larger sample size [139] where genotype data were assembled from a combined analysis of 16,731 samples. They successfully confirmed the genome-wide significance of CACNA1C and identified several other genetic regions, such as teneurin transmembrane protein (TENM4 [ODZ4]), ANK3,and spectrin repeat containing nuclear envelope protein 1 (SYNE1), to be related with bipolar. However, in the subsequent replication study with 46,912 samples, only 18 SNPs from CACNA1C and ODZ4 showed significant signals with the same effect direction. Results from a recent GWAS based on Japanese population support nuclear factor I X (NFIX), mitotic arrest deficient 1 like 1 (MAD1L1), tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1), and ODZ4 as susceptible genes associated with bipolar disease risk [140].
Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Tatsushi Toda, Shoji Tsuji
Mutations in the spectrin repeat containing nuclear envelope protein 1 gene (SYNE1) have been described to cause a slowly progressive pure cerebellar ataxia (spinocerebellar ataxia, autosomal-recessive 8; SCAR8/autosomal-recessive cerebellar ataxia type 1, ARCA1), which was originally identified in Quebec, Canada (5,6). Notably, recent studies revealed that cerebellar ataxia associated with SYNE1 variants was also observed outside Quebec or French-Canadian populations, and affected patients can present with complex phenotypes rather than pure cerebellar ataxia, including motor neuron and brainstem dysfunctions (6–8). We herein report the clinical and genetic presentations of a Japanese patient diagnosed with juvenile ALS, who carried compound heterozygous pathogenic variants, including a novel one, in SYNE1.
The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy
Published in Expert Opinion on Orphan Drugs, 2018
Simon Guiraud, David Roblin, Davies. E. Kay
The full length 74 exons of the utrophin gene encode a protein of 3433 amino acids with a predicted molecular weight of 395 kDa and 80% amino acid identity to dystrophin (Figure 3) [26]. Both proteins contain an actin-binding N-terminus, a triple coiled-coil spectrin repeat central region, and a C-terminus that consists of protein–protein interaction motifs which shares many binding partners, such as α-dystrobrevin-1, β-dystroglycan, and F-actin [27]. However, the two proteins show some differences. Both proteins bind actin filaments with similar affinity. However, molecular contact with actin filaments is operated through a unique continuous binding domain for utrophin. By contrast, dystrophin utilizes two low-affinity distinct and spatially separated actin-binding modules [28]. Utrophin also differs from dystrophin in its mode of interaction with microtubules [29]. Furthermore, utrophin does not recruit neuronal nitrogen synthase (nNOS) to the sarcolemma to regulate blood flow to muscles [30]. The significance of this observation is unclear; a recent study reported no relationship between the expression of nNOS at the sarcolemma and the disease severity in BMD patients [31] who remain mildly affected and ambulant without nNOS membrane localization, suggesting compensatory nNOS pathways.
Current and emerging pharmacotherapy for menstrual migraine: a narrative review
Published in Expert Opinion on Pharmacotherapy, 2023
Claire E. J. Ceriani, Stephen D. Silberstein
The menstrual cycle results from complex interactions between the hypothalamus, pituitary, ovary, and endometrium. Estrogen and progestins modulate neuronal activity and receptor density of central serotonergic and opioid neurons [10]. MM is triggered by the withdrawal of estrogen [11]; progesterone withdrawal does not precipitate migraine [12]. Changes in headache pattern associated with oral contraceptive use, menarche, menstruation, pregnancy, menopause, and hormone replacement therapy are related to changes in estrogen levels [10]. Animal studies have identified numerous brain areas involved in migraine pathophysiology that express estrogen receptors, including the hypothalamus, cerebral cortex, cerebral arteries, and trigeminal ganglia [13]. Several studies have investigated genetic factors in MM, predominantly looking at genes associated with estrogen, with conflicting results [14]. Single nucleotide polymorphisms (SNPs) in the spectrin repeat-containing nuclear envelope 1 (SYNE1) gene, which is adjacent to the estrogen receptor-1 gene, have been positively associated with MM [15]. SNPs in the neuropilin 1 gene (NRP1), which encodes a transmembrane protein, also are associated with MM [16].There is emerging evidence for the role of calcitonin gene-related peptide (CGRP) and oxytocin in MM. CGRP levels change during the menstrual cycle. Women with comorbid migraine and endometriosis have increased CGRP plasma levels in the menstrual phase, whereas healthy controls show a decrease [17]. Women also have higher levels of CGRP than men, and women taking oral contraceptives have higher levels than women not taking contraceptives [18]. Estrogen receptors, CGRP and its receptors, and oxytocin and its receptors are co-expressed in migraine-related nociceptive pathways in the central nervous system and in the peripheral trigeminal ganglia, suggesting functional interactions [19]. Estrogen increases both oxytocin and oxytocin receptor levels, and oxytocin has been shown to prevent migraine attacks [19]. Oxytocin has analgesic effects through multiple mechanisms, including inhibiting CGRP release from dural afferents and reducing the activation of central trigeminal nucleus caudalis neurons [20]. Both oxytocin and its receptor are altered during various reproductive states, and fluctuations in plasma levels during the menstrual cycle mirror those of estrogen [19]. The increased likelihood of a migraine attack during menstruation may result from modulation of endogenous oxytocin levels, oxytocin’s affinity for its receptor, and the expression of the receptor itself, all of which occur during menstruation [20]. It has been suggested that estrogen influences factors related to migraine within the trigeminal ganglia by modulating both CGRP and oxytocin signaling [19].