guanosine-triphosphate and Developmental-Disabilities

The efficacy of dopaminergic antagonists, which are neuroleptics, has been shown in children in varied clinical situations. Five dopaminergic receptors (D1, D2, D3, D4, D5) have thus far been cloned: their existence has thus been confirmed, but their functional significance remains to be determined. This publication reviews their main characteristics. The multiplicity of cerebral dopamine receptors is consistent with the future development of new, more selective and discriminating psychotropic drugs. The diversity of interactions of dopaminergic receptors, among themselves and with receptors for other neurotransmitters, however, explains the difficulty in understanding the mechanism of action of neuroleptics and defining their more rational use in children.

Topics: Adolescent; Antipsychotic Agents; Binding Sites; Brain; Cell Communication; Child; Child, Preschool; Cyclic AMP Response Element-Binding Protein; Developmental Disabilities; Dopamine; Female; Guanosine Triphosphate; Humans; Male; Receptors, Dopamine

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.

Topics: Developmental Disabilities; Facies; Genotype; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Intellectual Disability; Mitochondrial Proteins; Models, Molecular; Mutation; Mutation, Missense; Phenotype; Protein Conformation; Protein Interaction Domains and Motifs; ral GTP-Binding Proteins; ras Proteins

Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient in the enzyme purine nucleoside phosphorylase (PNP) and was present before development of T cell immunodeficiency. Guanosine triphosphate (GTP) depletion was noted in the erythrocytes of all surviving homozygotes and was of equivalent magnitude to that found in the Lesch-Nyhan syndrome (complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency). The similarity between the neurological complications in both disorders indicates that the two major clinical consequences of complete PNP deficiency have differing aetiologies: neurological effects resulting from deficiency of the PNP enzyme products, which are the substrates for HGPRT, leading to functional deficiency of this enzyme. immunodeficiency caused by accumulation of the PNP enzyme substrates, one of which, deoxyguanosine, is toxic to T cells. These studies show the need to consider PNP deficiency (suggested by the finding of hypouricaemia) in patients with neurological dysfunction, as well as in T cell immunodeficiency. They suggest an important role for GTP in normal central nervous system function.

Topics: Central Nervous System; Central Nervous System Diseases; Child; Child, Preschool; Deficiency Diseases; Developmental Disabilities; Erythrocytes; Female; Guanosine Triphosphate; Humans; Male; Pentosyltransferases; Purine-Nucleoside Phosphorylase