A novel c.59C&gt;T variant of the HSD17B10 gene as a possible cause of HSD10 mitochondrial disease with hepatic dysfunction: a case report and review of the literature

doi:10.21203/rs.3.rs-3924486/v1

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A novel c.59C>T variant of the HSD17B10 gene as a possible cause of HSD10 mitochondrial disease with hepatic dysfunction: a case report and review of the literature

https://doi.org/10.21203/rs.3.rs-3924486/v1

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Background

Pathogenic HSD17B10 gene variants cause HSD10 mitochondrial disease (HSD10 MD), which results in a wide spectrum of symptoms ranging from mild to severe. Typical symptoms include intellectual disability, choreoathetosis, cardiomyopathy, neurodegeneration, and abnormal behavior. This study aimed to investigate a novel c.59C > T variant of the HSD17B10 gene and the clinical phenotypic features of HSD10 MD (neonatal form) patients.

Results

We describe a 2-month and 12-day-old Chinese boy with intellectual disability, metabolic acidosis, hyperlactatemia, hypoglycemia, cholestatic hepatitis and myocardial enzyme levels, slightly elevated 2-methyl-3-hydroxybutyric acid (2M3HBA) levels and early death. Although full-length sequencing of the mitochondrial genome was normal, whole-exome sequencing of the proband and his parents revealed a novel de novo heterozygous variant, c.59C > T (p.S20L), of the HSD17B10 gene. Molecular dynamics simulation analysis and protein structural analysis have suggested that the c.59C > T (p.S20L) mutation may disrupt the conformational stability of the protein. According to the combined results of phenotypic analysis, molecular genetic analysis, protein structural analysis and molecular dynamics simulation analysis, this novel mutation is currently considered a likely pathogenic variant. HSD10 MD (neonatal form) can lead to hepatic dysfunction.

Conclusions

HSD10 MD (neonatal form) can lead to hepatic dysfunction. The de novo c.59C > T HSD17B10 variant suggested a neonatal form of the HSD10 mitochondrial disease phenotype in a 2-month and 12-day-old patient, broadening the variant spectrum of HSD17B10-related disease.

HSD10 mitochondrial disease

HSD17B10 gene

mutation

cholestatic hepatitis

metabolic disorder

HSD10 mitochondrial disease (OMIM 300438) was originally described as 2-methyl-3-hydroxybutyryl-l CoA dehydrogenase deficiency (MHBDD), a rare X-linked recessive genetic disorder. The multifunctional 17β-HSD10 protein is encoded by the HSD17B10 gene. The protein is widely distributed in various tissues and organs, mainly in the heart, liver and brain ^{[1, 2]}. Normal levels of 17β-HSD10 are essential for maintaining human health, especially normal cognitive function^[3]. The 17β-HSD10 protein plays an important role in the metabolism of isoleucine and branched-chain fatty acids^[3], neurosteroids, and sex steroid hormones^[4].

As a component of the mitochondrial RNase P protein complex^[5], 17β-HSD10 is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis^[6] and is essential for the structural and functional integrity of mitochondria^[7]. Indeed, complete loss of 17β-HSD10 is incompatible with life. The clinical symptoms of patients with HSD10 MD are unrelated to the accumulation of toxic metabolites in the isoleucine pathway and residual enzymatic activity of 17β-HSD10^[1]. Elevation of 2-methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG) in urine organic acid analysis can help in the diagnosis of HSD10 MD ^[6]. The pathology of HSD10 MD is thought to be caused by mitochondrial dysfunction^[7–10]. Pathogenic variants of the HSD17B10 gene cause HSD10 MD, the clinical features of which are similar to those of severe mitochondrial diseases (progressive neurodegeneration, cardiomyopathy and metabolic disorders). Since it was first reported in 2000^[2], relatively few cases worldwide have been reported in the literature^{[6, 11–13]}.

Here, we report a novel variant of the HSD17B10 gene (c.59C > T) in a 2-month-old and 12-day-old boy with a newly described aspect of the clinical phenotype of HSD10 MD, which manifested as intellectual disability, metabolic disorder, hyperlactatemia, cholestatic hepatitis, elevated myocardial enzymes and 2M3HBA levels and early death. We confirmed the pathogenicity of the strains by combining molecular genetic analysis, protein structural analysis, molecular dynamics simulation analysis and clinical analyses. We found that the neonatal form of HSD10 disease can lead to hepatic dysfunction.

The patient was a 2-month and 12-day-old Chinese boy who was admitted to our hospital because of jaundice. He was a full-term small baby (birth weight 2 kg, G1P1). Polypnea and jaundice were noted on the second day after birth. He was diagnosed with pneumonia, neonatal metabolic acidosis, hyperlactic acidaemia and neonatal hyperbilirubinemia in the hospital. His parents were healthy. He presented with intellectual disability, malnutrition (WT 3.6 kg), yellow skin, yellow sclera, and hepatomegaly but normal muscle strength and tension in his limbs. Laboratory examination revealed cholestasis, elevated transaminase and myocardial enzymes, hypoglycemia, hyperlactinemia, metabolic acidosis and anemia (Table 1). His plasma amino acid analysis was normal (proline, 92.97 µmol/L [reference range, 72–293]; alanine, 326.49 µmol/L [reference range, 62.9–500]). Gas chromatography–mass spectrometry (GC‒MS) of the urine sample revealed an increase in lactic acid (22.6; reference range, 0.0–13.0) and a slight increase in 2M3HBA (5.7; reference range, 0.0–4.0). The level of tiglylglycine was normal. Cardiac color Doppler ultrasound suggested a patent foramen ovale. Abdominal color Doppler ultrasound revealed a fine light spot in the liver and an enhanced echo. The patient was treated with reduced glutathione and ursodeoxycholic acid. The bilirubin level improved after treatment (Table 1). A month later, our patient had an upper respiratory infection and died while en route to the hospital.

Table 1

Changes and normal values of biochemical indicators in children
age	TBIL µmol/L	DBIL µmol/L	ALB g/L	GLO g/L	ALT IU/L	AST IU/L	γ-GGT IU/L	TBA µmol/L	LDH IU/L	CK U/L	CK-Mb U/L	LAC µmol/L	BS mmol/L
72 days	218.6	176.2	37.6	10.8	58.5	106.9	138.7	97.2	620	264	66.3	13.71	4.66
76 days	155.3	101.1	34.1	12.8	28.5	97	101	106.8	571	282.5	50.5	17.25	0.99
86 days	155.4	143.9	41.9	11.7	46.3	118.8	101.5	112.5	505	292	76.4	17.95	2.69
Normal range	3.4–17.0	0–6.0	35–55	20–35	0–40	0–40	0–50	0-9.67	0-450	38–174	0–24	0.5–2.44	3.9–6.1
TBIL = total bilirubin, DBIL = bilirubin direct, ALB = albumin, GLO = globulin, ALT = Alanine transaminase, AST = aspartate aminotransferase, γ-GGT = gamma-glutamyl transpeptidase, TBA = total bile acid, LDH = lactic dehydrogenase, CK = creatine kinase, CK-MB = Creatine kinase isoenzyme, LAC = lactic acid, BS = blood glucose

3.1 Patient and ethical considerations

The patient was managed at the Department of Hepatopathy Center, Hunan Children’s Hospital. Informed consent was obtained from the patients’ parents, and all clinical investigations were carried out in accordance with the Declaration of Helsinki^[14]. This study was approved by the Medical Ethics Committee of Hunan Children’s Hospital.

3.2 Genetic analysis

A 2 mL sample of peripheral blood in EDTA anticoagulant tubes was extracted from the child and his parents, and whole-exome sequencing and a full-length PLUS test of the mitochondrial genome were performed. Genomic DNA was extracted from peripheral blood using a Solpure Blood DNA Kit (Magen) according to the manufacturer’s instructions. The genomic DNA was then fragmented by a Q800R Sonicator (Qsonica) to generate 300–500 bp insert fragments. Paired-end libraries were prepared following the Illumina library preparation protocol. Custom-designed NimbleGen SeqCap probes (Roche NimbleGen, Madison, WI) were used for in-solution hybridization to enrich target sequences. Enriched DNA samples were indexed and sequenced on a NextSeq500 sequencer (Illumina, San Diego, California) with 100–150 cycles of single-end reads according to the manufacturer’s protocols. Primary data were generated in fastq format after image analysis, and base calling was conducted using the Illumina Pipeline. Sequence variants were annotated using population and literature databases, including the 1000 Genomes, dbSNP, GnomAD, ClinVar, HGMD and OMIM databases. The online software package was used to analyze the structure of the protein, predict the conserved domain and functional domain and perform multiple sequence alignment. Variant interpretation was performed according to the American College of Medical Genetics (ACMG) guidelines^[15]. Full-length amplification and sequencing of the mitochondrial genome were performed according to our previous methods ^[16].

3.3 Molecular Dynamic Simulation

The 3D structure of HSD17B10 was downloaded from the RCSB database (PDB ID: 1u7t). Chain B was used for visualization analysis and molecular dynamic simulation. The cofactor NAD + in the crystal structure was retained. The Mutagenesis Wizard in the PyMOL 1.7 package was used to construct the S20L mutant.

3.4 Conservation analysis and protein schematic structures

Furthermore, we performed a conservative analysis of the four mutant amino acid sequences (mutation types in neonatal-type patients) by screening HSD17B10 orthologs against the NCBI HomoloGene database (https://www.ncbi.nlm.nih.gov/homologene/?term=) via the transcript NM_004493. The selected homologous amino acid sequences were downloaded and visualized with Ugeneui. Three-dimensional structural models of HSD17B10 were predicted with the AlphaFold tool (https://AlphaFold.ebi.ac.uk/). Protein structure images were generated using the PDB file and PyMOL. Hydrogen bonds in the proteins were detected using PyMOL to predict changes in mutant stability.

4.1 Genetic analysis

A hemizygous variant of HSD17B10 was identified by whole-exome sequencing. The hemizygous mutation c.59C > T (p.S20L) is a missense mutation. The C to T mutation at position 59 in the coding region of the gene results in a change in amino acid 20 from serine to leucine. His parents did not carry this mutation (Fig. 1). This variant has not been recorded in the HGMD, PubMed, ClinVar or other databases. This variant has not been reported in related clinical cases. The mutation was determined to be de novo, with a low frequency (less than 0.001) in our reference population gene database. The region where the variation occurs is an important part of the protein, and the amino acid sequence is highly conserved in different species. Computer-aided analysis predicted that this variant is likely to affect protein structure/function. In summary, based on the clinical manifestations of the patient and family analysis, the mutation was classified as "class 2 - possibly pathogenic" according to ACMG variant classification guidelines (PMID: 25741868, 31690835). Full-length sequencing of the mitochondrial genome of peripheral blood showed normal results.

4.2 Molecular Dynamic Simulation

In the wild-type protein, Ser20 forms a strong hydrogen bond with the phosphate group of NAD+, but in the S20L mutant, this H-bond is broken by the side chain of Leu (Fig. 2a). We speculated that this H-bond is highly important for the stable binding of NAD+. Without these H-bonds, NAD + may not bind very well, thus influencing the catalytic activity of the enzyme. The number of hydrogen bonds between NAD + and the wild-type enzyme was apparently greater than that between NAD + and the mutant enzyme during the 50 ns molecular dynamic simulation (Fig. 2b). This indicated that NAD + could bind more stably to the wild-type enzyme than to the S20L mutant enzyme. We used the RMSD to determine the conformational fluctuations of the protein (or ligand) and NAD+. The S20L mutant had a much greater RMSD than the wild-type enzyme (Fig. 2c). NAD + bound to the mutant protein had a much greater RMSD value than that bound to the wild-type protein (Fig. 2d). This result indicated that NAD + strongly bound to the WT receptor protein. Next, we used the MMGBSA method to calculate the binding free energy between NAD + and the wild-type receptor protein (enzyme) or the mutant protein based on the molecular dynamic trajectory. NAD + has a stronger binding affinity for the wild-type protein than for the mutant protein (binding free energy, -83 vs. -62 kcal/mol). Figure 2e shows the structural alignment of the wild-type and mutant proteins after the 50 ns molecular dynamic run. The mutant protein has a more expanded conformation than the wild-type protein, consistent with its high RMSD value. Overall, the apparent impact of this variant on the conformational stability of the protein is relevant to the occurrence of clinical disease.

4.3 Conservation analysis and protein schematic structures

The mutation types in neonatal-type patients were c.59C > T (p.S20L), c.740A > G (p.N247S), c.677G > A (p.R226Q) and c.257A > G (p.D86G). A conservative analysis of the four mutant amino acid sequences is shown in Fig. 3a-Figure 3c. The amino acids N247, S20, and R226 are close to the amino acid D86, which was mutated in a clinically severely affected patient with preserved MHBD enzymatic function. Structural analysis of the Mut-HSD17B10 protein revealed that the identified mutation (p.S20L) changes the hydrophobic amino acid threonine to the hydrophilic amino acid leucine (Fig. 3d). Mutation (p.D86G) disrupted the intermolecular hydrogen bond between amino acid 86 and amino acid 84 (Fig. 3e). The p.R226Q mutation breaks the intermolecular hydrogen bond between amino acids 226 and 232 and results in the formation of a new hydrogen bond with amino acid 227 (Fig. 3fFigure 3f). Mutation (p.N247S) disrupted the intermolecular hydrogen bond between amino acid 247 and amino acid 193 (Fig. 3g). These mutations may impact the local secondary structure and molecular function of the protein.

The age of onset of HSD10 disease can range from newborn to early childhood. The most severely affected patients were males (hemizygous), while heterozygous females were generally asymptomatic or had only mild symptoms. HSD10 disease is characterized by progressive neurodegeneration and includes intellectual disability, language defects, bradykinesia, ataxia, epilepsy, visual and auditory disorders, hypotonia, cardiomyopathy and metabolic disorders. There are four clinical types of HELLP syndrome: the neonatal, infantile, juvenile and atypical/asymptomatic ^[1]. The most common type is the infantile form. The clinical features of our patient included intellectual disability, metabolic acidosis, hyperlactatemia, hypoglycemia, cholestatic hepatitis and myocardial enzyme levels; slightly elevated 2M3HBA levels; and early death. Whole-exome sequencing of the proband and his parents revealed a novel de novo heterozygous variant, c.59C > T (p.S20L), of the HSD17B10 gene. Combined with the highly characteristic clinical phenotype and molecular genetic analyses, HSD10 MD (neonatal form) was a likely diagnosis.

Hepatic involvement is a common feature of early-onset mitochondrial disease^[17]. Genetically confirmed mitochondrial disease was observed in 17% of children who presented with acute liver failure before the age of 2 years ^{[18, 19]}. The main organ manifestation of HSD10 disease is the central nervous system. The liver and kidneys are not usually affected by the infantile form ^[1]. Few patients with the neonatal form of HSD10 MD have been reported to date (Table 2). Two patients with the neonatal form had hepatic dysfunction ^{[8, 10]}. Chatfield et al.^[8] reported that infants had hepatomegaly. The histological features of the patients included micro- and macrovesicular steatohepatitis, disrupted mitochondrial architecture with a strongly increased number of mitochondria and abnormal cristae structure. Mitochondrial respiration and assembly are disrupted in HSD10 disease. Our patient also had hepatic dysfunction. Genetic tests did not reveal any other variants that were potentially causative of mitochondrial disease or liver disease. Thus, the incidence of hepatic dysfunction in neonates is relatively high (50%). Patients with hepatic dysfunction and metabolic derangement should be vigilant against HSD10 disease during the neonatal period.

Table 2

Genotypes and phenotypes summary in neonatal form of HSD10 MD
	Mutation	Sex	Onset age	Clinical feature	Brain MRI	Family history	Present status (age)
Patient 1 (this report)	c.59C > T(p.S20L)	M	2d	development retardation, metabolic acidosis, hyperlactatemia, hypoglycemia, Cholestatic hepatitis, elevated myocardial enzyme.	NA	Normal parents	Dead (3m)
Patient 2^[17]	c.740A > G (p.N247S)	M	1d	Metabolic acidosis, hypoglycemia, hypotonia, cyanosis, cardiomegalia, hyperlactatemia and hyperlactaturia	NA	sister is patient ,Normal mother	Dead (2 m)
Patient 3^[10]	c.677G > A (p.R226Q)	M	1 d	Developmental regression, metabolic acidosis, hypoglycemia, anemia, hyperamoniemia, thrombopenia, cuagulopathy, hepatic dysfunction, myoclonus, seizures, hypertrophic miocardiopathy	Isquemic lesions in nucleus	Normal mother	Dead (7 m)
Patient 4^[7]	c.257A > G(p.D86G)	M	NA	Neurological development, progressive hypertrophic cardiomyopathy	NA	NA	Dead (7 m)
Patient 5^[8]	c.740A > G(p.N247S)	M	1d	mildly encephalopathic, hyperlactatemia, hyperlactaturia, hyperammonemia, feeding difficulties, PDA(patent ductus arteriosus), anemia, thrombocytopenia,, elevated transaminases, cuagulopathy	restricted diffusion in the perirolandic white matter	NA	Dead (6 m)
Patient 6^[18]	c.677G > A(p.Arg226Gln)	M	1d	Polypnea, moan, hypoglycemia, hyperlactatemia, psychomotor retardation	a slightly deeper sulci in the cerebral hemisphere	NA	abandoned the treatment
NA: not available

The 17β-HSD10 protein is encoded by the HSD17B10 gene, which maps to chromosome Xp11.2 and consists of 6 exons. In total, 16 different missense variants and a splicing mutation are reported to cause HSD10 MD ^{[4, 11, 20–24]}. The mutation c.388C > T (p.R130C) is the most frequent variant ^[12]. At present, the reported mutation types in neonatal patients include c.740A > G (p.N247S), c.677G > A (p.R226Q) and c.257A > G (p.D86G). This study also revealed a new mutation that causes neonatal-type HSD10 disease. Protein structural analysis revealed that these mutations may impact local secondary structure and molecular function. The mutated amino acid D86 was found in a clinically severely affected child and caused severe disruption of mitochondrial morphology. The amino acid Q165 was observed in a clinically mildly affected child but with completely deficient MHBD enzyme activity^[7]. The amino acids N247^[8], S20, and R226 are close to the amino acid D86 and away from the amino acid Q165. These mutations may increase the likelihood of causing mitochondrial dysfunction, which can lead to disease. Furthermore, we classified the missense variant c.59C > T as a likely pathogenic candidate causing this proband’s clinical manifestations for the following reasons. First, this variant is not listed in the HGMD, PubMed, ClinVar or other databases or the related literature. Second, the clinical features of the patient were consistent with those of patients with the neonatal form of HSD10 MD. Third, the ACMG variant classification guidelines classify patients as "class 2 - possibly pathogenic". Molecular dynamic simulation and protein structural analysis revealed that the mutation may disrupt the conformational stability of the protein.

This study has several limitations. Brain MRI was not performed. Studies to determine the effect of the mutation on protein expression were not performed. Due to the early death of our patient, functional verification was not carried out. The same mutation can lead to different clinical manifestations. Due to the small number of cases reported thus far, additional evidence for a clear genotype–phenotype correlation is needed.

There is no effective therapy for HSD10 MD. Cardiac failure, Kussmaul breathing, and multiple-organ dysfunction may be induced by mild infection^[8]. Our patient had an upper respiratory tract infection before death. Therefore, rapid intervention in patients with acute infection is highly important.

In conclusion, HSD10 MD (neonatal form) can lead to hepatic dysfunction. Our results add evidence that the de novo variant c.59C > T (p.S20L) suggests HSD10 MD (neonatal form) in this 2-month and 12-day-old patient, broadening the spectrum of HSD17B10-related disease.

2M3HBA 2-methyl-3-hydroxybutyric acid

17β-HSD10 17β-hydroxysteroid dehydrogenase type 10

HSD10MD HSD10 mitochondrial disease

MD mitochondrial disease

RMSD root-mean-square deviation

MMGBSA molecular mechanics-generalized Born surface area

TG tiglylglycine

Acknowledgements

We would like to thank the patient and his family for their participation in this study.

Author contributions

SL, WO, and TJ conceived and designed the overall project. TJ and HY wrote the manuscript. All the authors approved the final manuscript for submission and agree to be accountable for all the aspects of the work.

Funding

This study had no Funding.

Availability of data and materials

The datasets generated and analyzed for this study were available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of the Hunan Children’s Hospital, and written informed consents were signed by the parents of all patients before this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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A novel c.59C>T variant of the HSD17B10 gene as a possible cause of HSD10 mitochondrial disease with hepatic dysfunction: a case report and review of the literature

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Abstract

Background

Results

Conclusions

Figures

1 INTRODUCTION

2 CASE REPORT

3 METHODS

3.1 Patient and ethical considerations

3.2 Genetic analysis

3.3 Molecular Dynamic Simulation

3.4 Conservation analysis and protein schematic structures

4 RESULTS

4.1 Genetic analysis

4.2 Molecular Dynamic Simulation

4.3 Conservation analysis and protein schematic structures

5 DISCUSSION

Abbreviations

Declarations

References

Status:

Version 1