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  • Updated 04.12.2021
  • Expires For CME 04.12.2024

HSD10 disease

Introduction

Overview

HSD10 disease is a rare X-linked disease with a wide spectrum of clinical and biochemical presentations in males. It is caused by pathogenic variants in the HSD17B10 gene. Dr. Johannes Zschocke, Professor of Human Genetics at the Medical University of Innsbruck, Austria, who first recognized the condition, explains that HSD17B10 encodes a moonlighting protein with at least 2 distinct functions that may be differentially affected with divergent clinical and biochemical effects. This is essential to understand for correct interpretation of clinical, biochemical, and molecular data.

Key points

• The X-chromosomal HSD17B10 gene encodes a moonlighting protein with at least 2 distinct functions, disruptions of which have diverse effects.

• The classical presentation of HSD10 disease is a progressive mitochondrial multisystem disease in boys thought to be due to deficient mtDNA transcript processing.

• Deficiency of the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase function of the protein causes typical biochemical abnormalities but may be asymptomatic.

• There is no effective treatment for HSD10 disease.

• Heterozygous females with pathogenic HSD17B10 variants are usually, but not always, asymptomatic.

Historical note and terminology

HSD10 disease was first described in 2000 as an atypical organic aciduria denoted 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (25). It is caused by mutations in HSD17B10 (denoted HADH2 at the time) located on chromosome Xp11.22 (13). The protein encoded by this gene is officially named 3-hydroxyacyl-CoA dehydrogenase type-2 but has been described with a range of other names, including 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD), 17-beta-hydroxysteroid dehydrogenase type 10 (HSD10), mitochondrial ribonuclease P protein 2 (MRPP2), short-chain dehydrogenases/reductases type 5 classical 1 (SDR5C1) (15), amyloid-binding alcohol dehydrogenase (ABAD), and others. It has a wide range of functions with sometimes uncertain relevance in humans. The most important function appears to be as a component of the mitochondrial ribonuclease P complex at the mitochondrial membrane. Ribonuclease P consists of 3 proteins (denoted MRPP1–3) and mediates the first step in the processing of the polycistronic mtDNA transcripts, ie, the modification and 3’ cleavage of tRNA sequences (10). The protein also catalyzes the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase reaction of isoleucine breakdown in the mitochondrial matrix (25). Various additional enzyme activities in bile acid and steroid hormone metabolism have been identified (19), but the in vivo relevance of these properties has not been confirmed in vivo. The protein has been reported to be involved in the pathogenesis of Alzheimer disease by binding amyloid beta (22), but again, the true relevance of this phenomenon is uncertain. HSD17B10 expression appears to be altered in some cancers, and overexpression or knock down was found to be associated with increased or reduced mtDNA levels, respectively (02). This may indicate a role of HSD10 in mtDNA maintenance.

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