rs137853097 — HSD17B4 N457Y

HSD17B4 N457Y — Hydratase Domain Failure in the Peroxisomal Fatty Acid Furnace

D-bifunctional protein (DBP), encoded by HSD17B4, is the enzymatic workhorse of peroxisomal beta-oxidation — the cellular pathway that shortens very long-chain fatty acids (VLCFAs), branched-chain fatty acids, and bile acid precursors that mitochondria cannot handle alone. The protein contains three sequentially arranged functional domains: a short-chain dehydrogenase/reductase unit, a 2-enoyl-CoA hydratase unit, and a sterol carrier protein 2 (SCP2) unit. Mutations in the hydratase domain cause type II DBP deficiency — an isolated block in the second step of peroxisomal beta-oxidation.

The N457Y variant is the second most common pathogenic mutation in HSD17B4¹¹ second most common pathogenic mutation in HSD17B4
Ferdinandusse et al. 2006 identified N457Y in 13 of 110 DBP-deficient patients, giving an allele frequency of ~11% among affected individuals, trailing only rs137853096 (p.Gly16Ser) in frequency. It was first characterized as a distinct disease entity by van Grunsven et al. in 1999.

The Mechanism

The N457Y substitution — asparagine to tyrosine at position 457 — falls within the 2-enoyl-CoA hydratase 2 unit²² 2-enoyl-CoA hydratase 2 unit
the enzyme that adds water across the double bond of enoyl-CoA substrates, converting them to 3-hydroxyacyl-CoA intermediates during each round of peroxisomal beta-oxidation. The bulky tyrosine side chain cannot accommodate the binding geometry required by the asparagine-containing pocket, leading to two compounding defects:

First, the full-length D-bifunctional protein is strongly destabilized. Second, the enoyl-CoA hydratase component that is normally cleaved from the full-length protein within peroxisomes becomes undetectable — the protein is degraded before it can be processed. The net effect is a near-complete block in the hydratase step, while the 3-hydroxyacyl-CoA dehydrogenase activity from the adjacent domain may be partially preserved. This biochemical profile defines type II DBP deficiency.

Because this variant specifically impairs the hydratase domain, the biochemical signature differs from total DBP deficiency: patients show elevated VLCFAs and branched-chain fatty acids (pristanic acid) but normal bile acid intermediates³³ patients show elevated VLCFAs and branched-chain fatty acids (pristanic acid) but normal bile acid intermediates
Bile acid synthesis uses a different step of the beta-oxidation cycle that requires the dehydrogenase unit, which is less affected in type II. This distinguishes type II DBP deficiency from the complete form and from Zellweger spectrum disorders.

The Evidence

DBP deficiency follows autosomal recessive inheritance. Two pathogenic alleles — either homozygous or compound heterozygous — are required to cause disease; single heterozygous carriers have normal peroxisomal function.

Van Grunsven et al. 1999⁴⁴ Van Grunsven et al. 1999 identified N457Y homozygous in two unrelated patients with isolated enoyl-CoA hydratase deficiency. Yeast expression studies confirmed the mutation was sufficient to cause the enzymatic defect. Both patients had severe neonatal presentations with hypotonia, seizures, and neuronal migration defects.

Mendes et al. 2015⁵⁵ Mendes et al. 2015 reported the first Portuguese case with homozygous N457Y: neonatal-onset seizures and hypotonia with neuroimaging showing polymicrogyria indistinguishable from Zellweger spectrum disease. The parents were confirmed carriers, enabling prenatal diagnosis for subsequent pregnancies.

Ferdinandusse et al. 2006⁶⁶ Ferdinandusse et al. 2006 characterized the mutational spectrum across 110 DBP-deficient patients: N457Y had an allele frequency of ~11% in the patient cohort. Among patients homozygous or compound heterozygous for hydratase-domain mutations, survival ranged from 1 to 26 months. The 8 patients who survived beyond 3 years all carried missense mutations with less structural disruption.

Pierce et al. 2010⁷⁷ Pierce et al. 2010 established that HSD17B4 mutations can cause Perrault syndrome — a milder allelic disorder characterized by sensorineural hearing loss and ovarian dysgenesis in females, without the catastrophic neonatal neurological crisis of classic DBP deficiency. The Perrault phenotype typically arises from compound heterozygous combinations where one allele is a severe loss-of-function and the other is a mild missense; the residual enzymatic activity is sufficient to prevent neonatal catastrophe but insufficient for normal gonadal and auditory development.

ClinVar classifies this variant as Pathogenic/Likely Pathogenic across multiple independent submissions, with functional experimental evidence (protein instability and enzymatic loss) supporting the classification.

Practical Actions

For the vast majority of people, this SNP returns the AA genotype — no pathogenic alleles. The T allele has an estimated global carrier frequency of roughly 1 in 500 to 1 in 1,000, making it the rarest of contexts in consumer genomics.

For heterozygous AT carriers: there is no clinical effect from a single copy. The peroxisomal beta-oxidation capacity of one functional HSD17B4 allele is sufficient for normal metabolic function throughout life. The relevance is exclusively reproductive — if both partners carry a pathogenic HSD17B4 allele (this one or rs137853096 or another), each pregnancy has a 25% chance of producing an affected child with DBP deficiency.

For homozygous TT carriers: this result would only arise in a clinical whole-genome sequencing context in a child with neonatal hypotonia, seizures, and elevated VLCFAs. Supportive care is the current management approach, focused on seizure control, nutritional support, and developmental monitoring.

Interactions

HSD17B4 has two well-characterized pathogenic missense variants: rs137853096 (p.Gly16Ser in the dehydrogenase domain, the most common DBP mutation) and rs137853097 (p.Asn457Tyr in the hydratase domain, the second most common). Compound heterozygosity for these two alleles — one inherited from each parent — is a recognized genotype causing DBP deficiency. In such compound heterozygotes, both enzymatic functions are compromised, typically producing the severe classic presentation. The two variants affect different domains, so neither is a subset of the other's functional defect: the dehydrogenase unit (rs137853096) and the hydratase unit (rs137853097) fail independently, resulting in combined type I/II biochemistry with elevations across VLCFAs, pristanic acid, and bile acid intermediates.

Any person who is a confirmed carrier of rs137853097 should have their partner tested for rs137853096 (and other HSD17B4 pathogenic variants) before conception if a child is planned, as compound heterozygosity is clinically equivalent to homozygosity for either variant alone in terms of reproductive risk.