Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Abstract

Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17␤) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD ؉ the Hill coefficient of the mutant enzyme is Ϸ1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the ␥-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17␤) dehydrogenase 10 deficiency.developmental disabilities ͉ HSD10 deficiency ͉ hydroxyacyl-CoA dehydrogenase

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

“…38 While SDR5C1 is ubiquitously expressed in all tissues, it is predominantly found in liver, heart, and brain. In the brain, it is primarily expressed in neural rather than in glial cells, implying that the loss of the dehydrogenase activity could cause neurodegeneration.…”

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…AF037438). The role of 17β-HSD10, after many debates and criticisms, has been clarified in more recent studies (163-174): it plays essential roles in neurosteroidogenesis as well as in the isoleucine degradation pathway. This explains why a mutation(s) of this gene, HSD17B10 , may delay the brain development and/or result in the regression of brain functions even in the absence of Aβ peptide (167, 168, 174-176).…”

“…As is well known, 17β-estradiol exhibits significant neuroprotective effects. Elevated levels of 17β-HSD10 found in Alzheimer's disease brains (164, 165, 168, 179) may take a part in the pathogenesis of Alzheimer's disease due to an imbalance of neuroactive steroid metabolism (164-170, 174, 177). …”

X-inactivation of HSD17B10 revealed by cDNA analysis in two female patients with 17β-hydroxysteroid dehydrogenase 10 deficiency

“…1,4-11 However, three patients were identified who presented symptoms in the first days of life. 1, 11 It has recently been shown that symptoms of these patients are unrelated to accumulation of metabolites in the isoleucine pathway and that the neurological handicap can be associated with an imbalance in neurosteroid metabolism 12 or to defects in general mitochondrial function. 13 In addition, the splice variant c.574C4A of HSD17B10 gene has been associated with a new syndromic form of X-linked mental retardation, choreoathetosis and abnormal behaviour.…”