Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from < 50kb to > 9Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

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Targeted modification of promoters

Genome editing for precision crop breeding - Burleigh Dodds Series in Agricultural Science ◽

10.19103/as.2020.0082.29 ◽

2021 ◽

pp. 247-278

Author(s):

Andika Gunadi ◽

◽

Ning Zhang ◽

John J. Finer ◽

◽

...

Keyword(s):

Gene Expression ◽

Genome Editing ◽

Promoter Region ◽

Regulatory Region ◽

Regulatory Elements ◽

Upstream Regulatory Region ◽

Precise Control ◽

Coding Regions ◽

Gene Coding ◽

Altered Regulation

Although most genome editing efforts focus on modifications to gene coding regions, this chapter emphasizes genome editing of the upstream regulatory regions. Thoughtful editing of the promoter region will ultimately lead to improved plants, modified for more precise control of the intensity and specificity of native gene expression. In this chapter, we present an overview of the promoter or upstream regulatory region of a gene, and describe how this sequence is defined and studied. We then describe how the composition and arrangements of cis-regulatory elements within the promoter and the leading intron associated with the promoter region have been studied using classical transgenic approaches to reveal what regulatory components might be suitable for genome editing approaches. Finally, we offer some suggestions for pursuit of promoter editing and gene expression modulation, which will eventually lead to modified plants with an altered regulation of native gene expression.

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Obstructive Sleep Apnea in a Patient with CHARGE Syndrome

Case Reports in Otolaryngology ◽

10.1155/2012/907032 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Carrie-Lee Trider ◽

Kim Blake

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Cranial Nerve ◽

Genetic Disorder ◽

Treatment Options ◽

Choanal Atresia ◽

Charge Syndrome ◽

Physical Symptoms ◽

Obstructive Sleep

CHARGE syndrome is a genetic disorder characterized by choanal atresia, coloboma of the eye, and ear and cranial nerve abnormalities. We report a child with CHARGE syndrome and obstructive sleep apnea. We highlight difficulties in discerning obstructive sleep apnea-related symptoms from typical features of CHARGE syndrome. Treatment options are discussed with regard to our patient. Tonsillectomy and adenoidectomy improved physical symptoms of obstructive sleep apnea in the patient.

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Abstract 228: A Novel Combinatorial Non-viral Vector to Treat Familial Hypercholesterolaemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.228 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Alastair G Kerr ◽

Lawrence Tam ◽

Milena Cioroch ◽

Ashley Hale ◽

Gillian Douglas ◽

...

Keyword(s):

Genomic Dna ◽

Transgene Expression ◽

Familial Hypercholesterolaemia ◽

Viral Vector ◽

Genetic Disorder ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Regulatory Elements ◽

Low Density ◽

Cholesterol Diet

Familial hypercholesterolaemia (FH) is a life-threatening genetic disorder characterised by elevated levels of plasma low density lipoprotein cholesterol (LDL-C). Loss-of-function mutations in the gene encoding the low density lipoprotein receptor (LDLR) are responsible for ~85% of all FH cases. Current attempts at gene therapy for FH have been limited by the use of strong heterologous promoters which lack regulatory elements essential for controlled expression. We have previously generated mini-gene vectors carrying the human LDLR cDNA, driven by 10 kb of genomic DNA from the native human LDLR locus, encompassing a promoter region with all essential elements required for physiologically regulated expression (pLDLR-LDLR). We demonstrated that incorporation of the genomic DNA promoter elements resulted in long-term physiologically-regulated LDLR transgene expression that complemented Ldlr deficiency. Here we further enhance LDLR transgene expression by characterising and cloning in a miRNA, targeting Hmgcr (miR82) generating a combinatorial RNAi-LDLR vector (pLDLR-LDLR-miR82). We show in vivo that the combinatorial vector efficiently suppresses endogenous Hmgcr transcripts, which leads to an increase in LDLR transgene expression through induction of the LDLR promoter. In a preliminary study the pLDLR-LDLR-miR82 vector was able to significantly reduce total and LDL-C, in Ldlr -/- mice fed a 1% cholesterol diet at two and four weeks post vector delivery. We then carried out a longer term study in Ldlr -/- mice fed a 0.25% cholesterol diet, LDLR expression could be detected 12-weeks post-delivery with the plasmid able to be rescued as a functioning episome. LDL-C was significantly lowered throughout the study and this resulted in reduced atherosclerosis in the pLDLR-LDLR-miR82 vector treated mice. Here we demonstrate for the first time, that an episomal non-viral vector is able to significantly reduce LDL-C and the progression of atherosclerosis in a mouse model of FH.

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Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.

Journal of Experimental Medicine ◽

10.1084/jem.173.5.1073 ◽

1991 ◽

Vol 173 (5) ◽

pp. 1073-1082 ◽

Cited By ~ 22

Author(s):

S Rodriguez de Cordoba ◽

P Sanchez-Corral ◽

J Rey-Campos

Keyword(s):

Acute Phase ◽

Polypeptide Chain ◽

Binding Protein ◽

Protein A ◽

Regulatory Elements ◽

Computer Search ◽

Functional Domain ◽

Coding Region ◽

Gene Coding ◽

Alpha Gene

The human gene coding for the 70-kD polypeptide of the complement regulatory component C4b-binding protein (C4BP alpha) spans over 40 kb of DNA and is composed of twelve exons. Upon transcription in liver, or in Hep-G2 cells, this gene produces a single transcript of 2,262 nucleotides, excepting the poly A tail, that presents an unusually long 5' untranslated region (5' UTR) of 223 nucleotides. The C4BP alpha gene is organized as follows: the first exon codes for the first 198 nucleotides of the 5' UTR. It is separated by a large intron from the second exon including the remaining of the 5' UTR and the coding region for the signal peptide. Each of the eight 60-amino acid repeats (short consensus repeats [SCRs]) that compose the C4BP alpha polypeptide chain is encoded by a single exon, except for the second SCR, which is split in two exons. At the 3' end of the C4BP alpha gene, the twelfth exon codes for the COOH-terminal 57 amino acids of the mature protein, which have no similarities to the SCRs, and the 245 nucleotides of the 3' UTR. Examination of the nucleotide sequence of the first exon revealed an interesting characteristic, strongly suggesting that this exon may specify a functional domain of the C4BP alpha transcript. It includes two in-phase ATG codons, in a different frame respect to that coding the C4BP alpha polypeptide, followed by an in-frame termination codon, also within the first exon. Comparison between mouse and human C4BP alpha transcripts indicates conservation of this structure within the 5' UTR. C4BP is expressed in the liver and is an acute phase protein. A computer search of the genomic sequences upstream the transcription start site demonstrates the presence of potential cis-acting regulatory elements similar to those found in the promoters of other liver-expressed and/or acute phase genes.

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The mediating effects of quality of life, depression, and generalized anxiety on perceived barriers to employment success for people diagnosed with Neurofibromatosis Type 1

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01866-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Frank D. Buono ◽

Matthew E. Sprong ◽

Erina Paul ◽

Staci Martin ◽

Kaitlyn Larkin ◽

...

Keyword(s):

Quality Of Life ◽

Neurofibromatosis Type 1 ◽

Genetic Disorder ◽

Neurofibromatosis Type ◽

Physical Symptoms ◽

Anxiety And Depression ◽

Successful Employment ◽

The Impact

Abstract Background Neurofibromatosis Type 1 (NF1) is a genetic disorder that presents with physical symptoms that can negatively impact numerous areas of one’s life, including occupational and psychological functioning, with decreased quality of life compared to a normative population. The purpose of the current study was to explore differences in the impact of psychological factors (anxiety and depression), quality of life and employment hope on barriers to successful employment between those with NF1 and matched controls. Methods A total of 212 individuals were stratified into two groups (NF1 and matched controls) using a cross-sectional design that collected a one-time response. Results A mediation analysis in which total barriers to successful employment on the differences between groups with quality of life, anxiety and depression as the mediators, and levels of employment hope as the co-variates were examined. The results confirmed a direct (.001) and indirect (< .001) relationship between barriers to successful employment with NF1 to matched controls, and with quality of life, anxiety, and depression. Conclusions The current findings indicate that the barriers to successful employment for individuals with NF1 impact their quality of life, anxiety, and depression more than that of the matched controls. Poorer barriers of employment observed amongst people with a genetic disease can impact mental health and quality of life.

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Computational prediction of CRISPR-impaired non-coding regulatory regions

10.1101/2020.12.22.423923 ◽

2020 ◽

Author(s):

Nina Baumgarten ◽

Florian Schmidt ◽

Martin Wegner ◽

Marie Hebel ◽

Manuel Kaulich ◽

...

Keyword(s):

Computational Prediction ◽

Regulatory Elements ◽

Cell Type ◽

Coding Regions ◽

Gene Coding ◽

Genome Wide ◽

A Genome ◽

Crispr Screen ◽

Genomic Regions ◽

Made In

AbstractGenome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.

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The Burden of Illness in Patients with Familial Chylomicronemia Syndrome (FCS) in the United Kingdom

10.21203/rs.2.14290/v1 ◽

2019 ◽

Author(s):

Handrean Soran ◽

Michael Stevenson ◽

Brant Hubbard ◽

Richard Jones ◽

Basil Issa

Keyword(s):

United Kingdom ◽

Disease Management ◽

Burden Of Illness ◽

Genetic Disorder ◽

Management Strategies ◽

Physical Symptoms ◽

Full Time ◽

The United Kingdom ◽

The Uk ◽

The Impact

Abstract Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with a deficiency in lipoprotein lipase activity, which is characterized by severe hypertriglyceridemia, recurrent abdominal pain and episodes of acute pancreatitis. Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients (IN-FOCUS) assessed the impact of FCS on patient quality of life (QoL) and quantified the burden of illness attributable to FCS for 166 patients in 10 countries. Given the lack of data to support value-based treatment of FCS in the United Kingdom (UK), a prespecified sub analysis of respondents from the UK was performed to evaluate country-specific experiences for patients with FCS and any associated outcomes. Methods: A web-based survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions from adults living with FCS. Results: Twenty respondents from the UK completed the survey. Three-quarters indicated that FCS limits their life and significant time and energy is required to manage their FCS. Respondents reported moderate physical symptoms 1–3 times every 2 weeks, all respondents reported worrying about their FCS getting worse with age and 85% worrying about the long-term impact of FCS on their health. Only 3 respondents (15%) reported working full-time,53% of respondents reported that their diminished employment was largely or entirely due to FCS. Furthermore, 90% of respondents reported restricting their dietary fat consumption to an extreme degree and 75% reported using fasting to help manage the symptoms of FCS, suggesting a level of overcompensation. Only one of five women reported a pregnancy. The UK data was largely consistent with the overall study, except for an increased prevalence of worry and differences in disease management. Conclusions: FCS is associated with an ongoing physical and emotional burden that negatively impacts QoL for patients in the UK. Attempts to self-manage FCS may increase the burden of disease. Results from the UK sub analysis are consistent with the overall cohort of IN-FOCUS in suggesting that increased disease awareness and improved management strategies for FCS are required.

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Analysis of regulatory elements of the promoter and the 3′ untranslated region of the maize Hrgp gene coding for a cell wall protein

Plant Cell Reports ◽

10.1007/s00299-003-0602-0 ◽

2003 ◽

Vol 21 (9) ◽

pp. 916-923 ◽

Cited By ~ 12

Author(s):

M. Menossi ◽

F. Rabaneda ◽

P. Puigdomènech ◽

J. A. Martínez-Izquierdo

Keyword(s):

Cell Wall ◽

Untranslated Region ◽

Regulatory Elements ◽

Cell Wall Protein ◽

Gene Coding ◽

A Cell

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Medically Unexplained Physical Symptoms: Toward an Alternative Paradigm for Diagnosis and Treatment

CNS Spectrums ◽

10.1017/s1092852900008245 ◽

2003 ◽

Vol 8 (S3) ◽

pp. 20-26 ◽

Cited By ~ 13

Author(s):

Christos A. Ballas ◽

Jeffrey P. Staab

Keyword(s):

Chronic Pain ◽

Chest Pain ◽

Physical Symptom ◽

Physical Symptoms ◽

Medically Unexplained Physical Symptoms ◽

Axis I Disorders ◽

Medically Unexplained ◽

Axis I ◽

Unexplained Physical Symptoms ◽

Medical Symptoms

AbstractThe treatment of patients with unexplained medical symptoms is difficult because there is neither a clear etiology for the symptoms, nor a useful paradigm with which to understand and treat them. Patients with such symptoms are often referred to psychiatry with vague diagnoses of “somatization” or “hypochondriasis.” Rather than considering somatoform diagnoses based on the number or diversity of physical symptoms, evolving research suggests an emphasis on the type of physical symptom as an indicator of Axis I pathology. This article links specific symptomatic complaints, such as chronic pain, chest pain, and dizziness, to the respective Axis I disorders associated with them, such as depression, panic disorder, and anxiety disorders.

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