10 research outputs found
Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154348/1/ana25676.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154348/2/ana25676_am.pd
Biallelic inherited SCN8A variants, a rare cause of SCN8Aârelated developmental and epileptic encephalopathy
ObjectiveMonoallelic de novo gainâofâfunction variants in the voltageâgated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic lossâofâfunction variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or lossâofâfunction are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wildâtype allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A.MethodsWe identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells.ResultsWe identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete lossâofâfunction, and one allele with altered biophysical properties consistent with partial lossâofâfunction.SignificanceThese studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/1/epi16371_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/2/epi16371.pd
Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers âŒ99% of the euchromatic genome and is accurate to an error rate of âŒ1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
Background: New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.
Methods: The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the
anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs
vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or
onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival
was evaluated at 7â15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ
and rifapentine (RIFAP) against male Onchocerca.
Results: WT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001).
IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID
responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ
induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN
induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in
SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs
39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7
days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted
SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99%
in implanted SCID receiving RIFAP for +2 weeks.
Conclusions: We have developed a âpan-filarialâ small animal research model that is sufficiently robust, with adequate
capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine
onchocercoma xenograft model is achievable
Genes and genetics in hyperhomocysteinemia and the â1-carbon metabolismâ: implications for retinal structure and eye functions
Homocysteine (Hcy); a sulfur-containing non-proteinogenic amino acid is generated as a metabolic intermediate. Hcy constitutes an important part of the â1-carbon metabolismâ during methionine turnover. Elevated levels of Hcy known as hyperhomocysteinemia (HHcy) results from vitamin B deficiency, lack of exercise, smoking, excessive alcohol intake, high fat and methionine rich diet, and the underlying genetic defects. These factors directly affect the â1-carbon metabolism (methionine-Hcy-folate)â of a given cell. In fact, the Hcy levels are determined primarily by dietary intake, vitamin status, and the genetic blueprint of the susceptible individual. Although Hcy performs important role in cellular functions, but genetic alterations in any of the key enzymes responsible for the â1-carbon metabolismâ could potentially upset the metabolic cycle thus causing HHcy environment in susceptible people. As such HHcy relates to several clinical conditions like atherosclerosis, myocardial infarction, stroke, cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and the ocular disorders among others. This manuscript sums up the findings from our laboratory and public database regarding genetics of HHcy and its effects on ocular disorders, their respective management during dysregulation of the 1-carbon metabolism.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author