Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts.
Methods
TheTPHintron 7 A218C polymorphism was determined using a polymerase chain reaction–based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects.
Results
There was a significant association betweenTPHgenotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found betweenTPHalleles and suicidal behavior.
Conclusions
This result suggests the involvement of theTPHgene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.
Editor—Huntington’s disease (HD) is an autosomal dominant disorder characterised by the association of choreic movements and cognitive/psychiatric changes. In 1993, the HD Collaborative Research Group reported the identification of the IT15 gene, which encodes a protein named huntingtin that carries an unstable and expanded CAG repeat in patients.1 Normal alleles are polymorphic with 11 to 35 CAG repeats, whereas expanded alleles in patients contain 36 or more repeats.
HD is thought to be a true dominant disorder, since homozygous carriers of the disease are no more severely affected than heterozygous carriers.2 However, precise clinical evaluations have not yet been reported in homozygous patients with known expansion sizes. We report here the clinical, neuropsychological, and molecular characterisation of such a patient in comparison to his heterozygous brother.
The patients underwent neurological examination, including the motor scale of HD,3 neuropsychological testing known to be sensitive to subcortical dementia.4 CAG repeats of the IT15 gene were sized by PCR using Hex labelled primer HD1 and HD2.5 PCR products were run on a 4% polyacrylamide gel and the CAG repeat was estimated using Genescan and the Genotyper software package.
Three HD patients (IV.4, IV.5, and IV.6) were born to parents who were first cousins (fig 1). The mother (III.2), who died at the age of 62, was known to be affected by history but age at onset could not be determined. The father (III.1, 20/41 CAG repeats), examined at the age of 68, had severe choreic movements (motor score 16/20), dysarthria, and cognitive changes with a Mini Mental State examination of 13/30, but was not aware of his symptoms …
Eighty-five young Mauritian Indians, male survivors of premature myocardial infarction (MI) and thus belonging to a high risk group, were compared with 108 stringently selected controls for a possible association between premature MI and an insertion/deletion (I/D) polymorphism in the gene encoding angiotensin I-converting enzyme (ACE). The frequency of the D allele was 0.42 in the MI group and 0.43 in the control group, and thus no association between I/D polymorphism of ACE with susceptibility to early-onset MI was found in this population group. Other gene components of the renin-angiotensin system and lipid metabolism need to be explored to understand the genetic factors involved in causing MI at an early age.
Abstract Since the beginning of the cloning of human disease‐causing genes and the identification of gene mutations, in most cases of Mendelian disorders a clear correlation between a given genotype and a particular phenotype has not been established. Understanding the complex relationships between genotypes and phenotypes is one of the greatest challenges of genetic medicine, because the elucidation of these correlations is the key to using genetic diagnosis and DNA‐based tests for the diagnosis, prognosis and surveillance of individuals affected by genetic conditions.
The risk for birth defects in the offspring of first cousin parents is substantially higher than in the offspring of non-consanguineous parents. As a general decline in the frequency of consanguineous marriages was observed in this century, one wonders whether consanguinity is still a factor in the appearance of birth defects in developed countries. Based on our registry of congenital anomalies, we think that the answer to this question is "yes." In the population studied in Northeastern France, consanguineous matings were known in 1.08% of the cases with congenital anomalies, vs. 0.28% in controls (P < 0.001). The frequency of the malformations recorded paralleled the degree of consanguinity: out of 38 malformed children, 24 were seen in first cousin matings (10.5 times more frequent than in offspring of nonconsanguineous couples), 8 in second cousin marriages, and 6 in more distantly consanguineous matings. Consanguineous mothers were more often pregnant than nonconsanguineous mothers (P < 0.01) and they had more stillbirths than nonconsanguineous mothers. These results must be taken into account when counseling consanguineous couples.
The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.
