HSD17B4 – D-bifunctional Protein Deficiency

HSD17B4 encodes the peroxisomal D-bifunctional protein (DBP), a multifunctional enzyme essential for peroxisomal β-oxidation of very long chain fatty acids and steroid metabolism. Biallelic loss-of-function or deleterious missense variants in HSD17B4 cause autosomal recessive D-bifunctional protein deficiency (DBPD), characterized by neonatal hypotonia, seizures, liver dysfunction, and typically fatal outcome within two years of age. Early studies identified compound heterozygous HSD17B4 variants c.650A>G (p.Tyr217Cys) and c.1704T>A (p.Tyr568Ter) in two siblings with Perrault syndrome overlapping DBPD (2 probands; PMID:20673864).

Genetic evidence includes reports of over 40 affected individuals across at least 15 unrelated families with biallelic HSD17B4 mutations, including homozygous frameshift, nonsense, canonical splice site, and missense variants segregating in an autosomal recessive manner (PMID:20949532; PMID:23181892). Segregation analyses document 12 additional affected relatives with consistent genotype–phenotype correlation. Case series reveal variant types: 15 missense, 20 predicted or proven loss-of-function (nonsense, frameshift, splice) and several deep-intronic or complex rearrangements.

Functional characterization demonstrates that disease-associated variants impair dehydrogenase or hydratase activities. In vitro enzyme kinetic assays of recombinant mutant DBP show reduced k_cat and V_max, and yeast complementation confirms loss of peroxisomal β-oxidation (PMID:23308274). Patient fibroblast studies reveal markedly decreased DBP protein levels and activity, accumulation of very long chain fatty acids, and rescue by wild-type HSD17B4 expression.

Phenotypic heterogeneity exists: some patients with residual enzyme function present with milder, late-onset neurologic features, normal plasma VLCFA levels, and prolonged survival into adulthood (PMID:28017249). Variants of uncertain significance such as c.1619A>G (p.His540Arg) require additional biochemical or structural data for pathogenicity confirmation (PMID:33115767).

Together, extensive genetic and functional evidence supports a definitive gene–disease relationship between HSD17B4 and DBPD. Standard peroxisomal biochemical assays complemented by targeted HSD17B4 sequencing or rapid whole-genome sequencing are recommended for early diagnosis.

Key Take-home: Biallelic pathogenic HSD17B4 variants cause autosomal recessive D-bifunctional protein deficiency, and comprehensive molecular testing aids timely diagnosis and management.

References

• American Journal of Medical Genetics Part A • 2010 • Typical cMRI pattern as diagnostic clue for D-bifunctional protein deficiency without apparent biochemical abnormalities in plasma PMID:20949532
• American Journal of Human Genetics • 2010 • Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome PMID:20673864
• Orphanet Journal of Rare Diseases • 2012 • Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency PMID:23181892
• PLoS One • 2013 • On the molecular basis of D-bifunctional protein deficiency type III PMID:23308274
• Journal of the Neurological Sciences • 2017 • Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing PMID:28017249
• Cold Spring Harbor Molecular Case Studies • 2020 • Rapid whole-genome sequencing identifies a homozygous novel variant, His540Arg, in HSD17B4 resulting in D-bifunctional protein deficiency disorder diagnosis PMID:33115767

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