tretinoin and Intellectual-Disability

One of the defining features of the nervous system is its ability to modify synaptic strength in an experience-dependent manner. Chronic elevation or reduction of network activity activates compensatory mechanisms that modulate synaptic strength in the opposite direction (i.e. reduced network activity leads to increased synaptic strength), a process called homeostatic synaptic plasticity. Among the many mechanisms that mediate homeostatic synaptic plasticity, retinoic acid (RA) has emerged as a novel signaling molecule that is critically involved in homeostatic synaptic plasticity induced by blockade of synaptic activity. In neurons, silencing of synaptic transmission triggers RA synthesis. RA then acts at synapses by a non-genomic mechanism that is independent of its well-known function as a transcriptional regulator, but operates through direct activation of protein translation in neuronal dendrites. Protein synthesis is activated by RA-binding to its receptor RARα, which functions locally in dendrites in a non-canonical manner as an RNA-binding protein that mediate RA's effect on translation. The present review will discuss recent progress in our understanding of the novel role of RA, which led to the identification of RA as a critical synaptic signaling molecule that mediates activity-dependent regulation of protein synthesis in neuronal dendrites. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

Topics: Child Development Disorders, Pervasive; Homeostasis; Humans; Intellectual Disability; Neuronal Plasticity; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Synapses; Tretinoin

Tyrosinemia II is caused by a deficiency of hepatic tyrosine aminotransferase. With the deficiency of this key enzyme of tyrosine catabolism there is an increase in plasma tyrosine and then an increase in tyrosine metabolites in the urine. The increased plasma tyrosine causes tyrosine to crystallize in the cornea, producing corneal ulcerations and sometimes proliferation of corneal epithelium. In the epidermis of the palms and soles, tyrosine leads to erosions, crusting, and then hyperkeratosis. The human disease is due to an autosomal recessive gene, and similar genetic diseases have been found in mink and in dogs. A nutritional model for the disease, in which a high-tyrosine low-protein diet is fed to rats, produces almost identical features. The features of this disorder and some of the implications of this disease for the study of other genetic diseases is discussed in this review.

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Animals; Ascorbic Acid; Child; Child, Preschool; Eye; Female; Genetic Carrier Screening; History, 20th Century; Humans; Infant; Infant, Newborn; Intellectual Disability; Isomerism; Isotretinoin; Male; Pyridoxine; Rats; Skin; Tretinoin; Tyrosine; Tyrosine Transaminase

In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.

Topics: Adolescent; Alcohol Oxidoreductases; Alleles; Brain; Cell Nucleus; Cerebellum; Child; Child, Preschool; Chlorides; Chromosome Mapping; Cytoplasm; Exome Sequencing; Female; Frameshift Mutation; Genetic Variation; Genotype; HEK293 Cells; Homozygote; Humans; Infant; Intellectual Disability; Ions; Magnetic Resonance Imaging; Male; Mutagenesis, Site-Directed; Mutation; Oligonucleotide Array Sequence Analysis; Pakistan; Pedigree; Receptors, G-Protein-Coupled; Retina; RNA, Small Interfering; Signal Transduction; Tretinoin

Human alpha-fetoprotein is a pregnancy-associated protein with an undetermined physiological role. As human alpha-fetoprotein binds retinoids and inhibits estrogen-dependent cancer cell proliferation, and because retinoic acid (a retinol metabolite) and estradiol (an estrogen) can both initiate cellular gene transcription, it is hypothesized here that alpha-fetoprotein functions during critical gestational periods to prevent retinoic acid and maternal estradiol from inappropriately stimulating gene expression in developing brain regions which are sensitive to these chemicals. Prenatal/maternal factors linked to increased autism risk include valproic acid, thalidomide, alcohol, rubella, cytomegalovirus, depression, schizophrenia, obsessive-compulsive disorder, autoimmune disease, stress, allergic reaction, and hypothyroidism. It will be shown how each of these risk factors may initiate expression of genes which are sensitive to retinoic acid and/or estradiol - whether by direct promotion or by reducing production of alpha-fetoprotein. It is thus hypothesized here that autism is not a genetic disorder, but is rather an epigenetic disruption in brain development caused by gestational exposure to chemicals and/or conditions which either inhibit alpha-fetoprotein production or directly promote retinoic acid-sensitive or estradiol-sensitive gene expression. This causation model leads to potential chemical explanations for autistic brain morphology, the distinct symptomatology of Asperger's syndrome, and the differences between high-functioning and low-functioning autism with regard to mental retardation, physical malformation, and sex ratio. It will be discussed how folic acid may cause autism under the retinoic acid/estradiol model, and the history of prenatal folic acid supplementation will be shown to coincide with the history of what is popularly known as the autism epidemic. It is thus hypothesized here that prenatal folic acid supplementation has contributed to the post-1980 increase in US autism diagnoses. In addition to explaining the epidemic within the wider retinoic acid/estradiol model of causation, this theory leads to potential explanations for certain genetic findings in autism, autistic regression, and changing trends in autism symptomatology with regard to mental retardation, wheat allergy, and gastrointestinal problems.

Topics: alpha-Fetoproteins; Animals; Asperger Syndrome; Autistic Disorder; Cell Proliferation; Epigenesis, Genetic; Estradiol; Gastrointestinal Diseases; Gene Expression Regulation, Developmental; Humans; Intellectual Disability; Rats; Regression Analysis; Risk; Risk Factors; Transcription, Genetic; Treatment Outcome; Tretinoin

The tau4 domain in the extreme carboxyl (C) terminal region of thyroid hormone receptor (TR) is important to transactivation. We identified three truncated TRbeta1s with 11 (F451X), 13 (E449X) and 16 (C446X) amino acid deletions within this domain in subjects with resistance to thyroid hormone (RTH). F451X and C446X were found in a 6-year-old Japanese girl and a 31-year-old American male, respectively, who had both severe mental retardation. E449X was identified in a 16-year-old Japanese boy with no remarkable clinical symptoms except for goiter. Transient expression study revealed that all three mutants had negligible T3 binding and transcriptional activities. Each mutant TRbeta1 exhibited not only very strong dominant negative activity against wild TRbeta1, but also marked silencing activity. Interestingly, the dominant negative activity and silencing activity were significantly stronger in F451X than in E449X and C446X (P < 0.05). Gel-shift experiments revealed no apparent differences in homodimer formations of wild-type or mutant TRbeta1 proteins and in heterodimer formations with retinoid X receptor (RXR). These observations indicate that the tau4 domain affects diverse TR functions, and that the region between 11 and 13 C-terminal amino acids influences ligand-independent TR functions, including dominant negative and silencing activities. The central nervous system involvement is not necessarily determined by the dominant negative potency of the mutant TRbeta1 and other environmental or genetic factors may influence the RTH manifestations.

Topics: Adolescent; Adult; Animals; Base Sequence; Child; COS Cells; Dimerization; DNA; DNA Probes; Drug Resistance; Female; Goiter; Humans; In Vitro Techniques; Intellectual Disability; Male; Receptors, Thyroid Hormone; Recombinant Proteins; Sequence Deletion; Thyroid Hormone Resistance Syndrome; Transcriptional Activation; Transfection; Tretinoin; Triiodothyronine