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  • Updated 09.24.2023
  • Released 04.12.2021
  • Expires For CME 09.24.2026

HSD10 disease



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 two 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 two 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 (22). 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), and others (19). It is a moonlighting protein with two different and unrelated functions. In the mitochondrial matrix, it serves as a NAD-dependent dehydrogenase with primary relevance in isoleucine breakdown (MHBD function), and the disturbance of this function led to the identification of HSD10 disease (22). Clinically more relevant is the function as a component of the mitochondrial ribonuclease P complex at the mitochondrial membrane. Ribonuclease P consists of a HSD10 tetramer, the methyltransferase protein TRMT10C, and the nuclease protein PRORP (03) and mediates the first step in the processing of the polycistronic mtDNA transcripts, ie, the modification and 3’ cleavage of tRNA sequences (10). Various additional enzyme activities in bile acid and neurosteroid hormone metabolism have been identified in vitro (15; 17), but there is now evidence that they are clinically important. Wohlfarter and colleagues argued that evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro: the combination of an essential structural with a nonessential enzymatic function in the same protein may direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket (19). Thus, activities measured with purified enzyme do not necessarily reflect physiological relevance. 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, but the true role of HSD10 in cancer development remains to be characterized (17).

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