Dominant-negative variants in CBX1 cause a neurodevelopmental disorder.

PURPOSE: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1ß (HP1ß), as a cause of a novel syndromic neurodevelopmental disorder. METHODS: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays and neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. RESULTS: In 3 unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1ß, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1ß binding to heterochromatin, whereas HP1ß interactome analysis demonstrated that the majority of HP1ß-interacting proteins remained unchanged between the wild-type and mutant HP1ß. CONCLUSION: These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1ß chromatin binding during neurocognitive development. Because HP1ß forms homodimers and heterodimers, mutant HP1ß likely sequesters wild-type HP1ß and other HP1 proteins, exerting dominant-negative effects.

Effect of magnesium sulfate on plasma endothelin-1 levels in normal and preeclamptic pregnancies.

OBJECTIVE: We attempted to determine the effects of magnesium sulfate on: (1) endothelin-1 concentration in preeclampsia, preterm labor, and term pregnancy and (2) endothelin-1 release from human umbilical cord endothelial cells. STUDY DESIGN: Plasma samples were prospectively collected from eight women with preeclampsia, six preterm labor patients, and eight term patients undergoing external cephalic version before and 2 hours after magnesium sulfate infusion. Supernatants were collected from human umbilical cord endothelial cells exposed to magnesium sulfate and controls. All samples were assayed with a specific radioimmunoassay for endothelin-1. Paired Student t test and analysis of variance were used for statistical analysis. RESULTS: Magnesium sulfate infusion in preeclampsia lowered endothelin-1 levels compared with preinfusion values (6.6 +/- 3.81 before and 4.75 +/- 2.28 after infusion, p < 0.02). Magnesium sulfate did not have an effect on endothelin-1 concentration in preterm and term pregnancies. Magnesium sulfate did not alter the endothelin-1 release from human umbilical cord endothelial cells. CONCLUSION: A significant reduction of endothelin-1 plasma levels after magnesium sulfate therapy is limited to preeclampsia. In contrast, this lowering effect was not exhibited in women without preeclampsia or in normal endothelial cells.

Prenatal diagnosis and heterozygote detection by DNA analysis in ornithine transcarbamylase deficiency.

This report summarizes our experience with DNA analysis using a complementary DNA probe for ornithine transcarbamylase in 24 individuals or families with deficiency of this enzyme. In four cases, including three reported elsewhere, a Taql restriction site alteration directly detected the mutation. In 10 additional cases, only an affected male was available, and results of DNA analysis using the Taql enzyme were normal. In 10 cases, family studies were performed with the use of restriction fragment length polymorphisms. Prenatal diagnostic studies were performed for three informative pregnancies, and two affected male fetuses were identified. Analysis of two restriction fragment length polymorphisms, Mspla and BamHl, was informative in 14 of 19 (74%) known carrier females and in 21 of 35 (60%) females (the total number studied). One female previously predicted to be a noncarrier by protein-loading test was determined to be a carrier by analysis of restriction fragment length polymorphisms. The frequency of Taql site alterations was 4 of 24 families (17%). These data illustrate the importance of DNA analysis, pedigree analysis, and biochemical testing in families with ornithine transcarbamylase deficiency to detect carriers and establish the diagnosis prenatally.

Phenylalanine hydroxylase expression in liver of a fetus with phenylketonuria.

The expression and activity of phenylalanine hydroxylase was studied in the liver of a fetus aborted after prenatal diagnosis of phenylketonuria. No phenylalanine hydroxylase enzymatic activity or immunoreactive protein was detectable in the PKU liver specimen, though both enzymatic activity and immunoreactive protein were detectable in control specimens of similar gestational age. Phenylalanine hydroxylase messenger RNA of normal size was present in the PKU fetal liver at normal abundance. These results confirm the genetic diagnosis of PKU in this fetus and indicate that the mutations in this fetus affect translation or stability of the phenylalanine hydroxylase protein.

Geographical studies on rheumatoid arthritis

The prevalence of rheumatoid arthritis has been compared in eight population samples in America and Europe, in which routine x rays were taken of the hands and feet. All the x rays were read by one observer. No relationship to lattitude was discovered. The prevalence of "definite" arthritis was not significantly different in the three racial groups included in these surveys, but "probable" disease was more common in the Negro population in Jamaica than in the Amerindians or Caucasians. Radiological evidence of erosive arthritis was more frequent in the Jamaican than in the Amerindian, and the Amerindian than the Caucasian. Serological tests for rheumatoid factor were more often positive in the Amerindian and erosive changes more severe. The implications of these findings are discussed.(Summary)