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Normal Function
The HSD17B4 gene provides instructions for making the D-bifunctional protein. This protein is an enzyme, which means that it helps specific biochemical reactions take place. D-bifunctional protein is so named because it aids in two biochemical reactions.
The D-bifunctional protein is found in sac-like cell structures (organelles) called peroxisomes, which contain a variety of enzymes that break down many different substances. The D-bifunctional protein is involved in the breakdown of certain molecules called fatty acids. The protein has two separate regions (domains) with enzyme activity, called the hydratase and dehydrogenase domains. These domains help carry out the second and third steps, respectively, of a process called the peroxisomal fatty acid beta-oxidation pathway. This process shortens the fatty acid molecules by two carbon atoms at a time until the fatty acids are converted to a molecule called acetyl-CoA, which is transported out of the peroxisomes for reuse by the cell.
Health Conditions Related to Genetic Changes
D-bifunctional protein deficiency
More than 60 HSD17B4 gene mutations have been identified in individuals with D-bifunctional protein deficiency, a severe disorder that causes deterioration of nervous system functions (neurodegeneration) beginning in infancy. HSD17B4 gene mutations that cause D-bifunctional protein deficiency can affect one or both of the enzymatic activities of D-bifunctional protein; however, this distinction does not seem to affect the severity or features of the disorder.
Impairment of one or both of the D-bifunctional protein's enzymatic activities prevents it from breaking down fatty acids efficiently. As a result, these fatty acids accumulate in the body. It is unclear how fatty acid accumulation leads to the specific features of D-bifunctional protein deficiency; however, the accumulation may result in abnormal development of the brain and the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. Destruction of myelin leads to a loss of myelin-containing tissue (white matter) in the brain and spinal cord; loss of white matter is described as leukodystrophy. Abnormal brain development and leukodystrophy likely underlie the neurological abnormalities that occur in D-bifunctional protein deficiency.
More About This Health ConditionPerrault syndrome
At least two HSD17B4 gene mutations have been found to cause Perrault syndrome, a condition characterized by hearing loss in affected males and females and ovarian abnormalities in affected females. The HSD17B4 gene mutations involved in this condition reduce the amount of functional D-bifunctional protein that is produced. It is not known what effect these mutations have on fatty acid breakdown in affected individuals or how the mutations lead to the signs and symptoms of Perrault syndrome.
More About This Health ConditionOther Names for This Gene
- 17-beta-HSD 4
- 17-beta-HSD IV
- 17-beta-hydroxysteroid dehydrogenase 4
- 17beta-estradiol dehydrogenase type IV
- 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholest-24-enoyl-CoA hydratase
- beta-hydroxyacyl dehydrogenase
- beta-keto-reductase
- D-3-hydroxyacyl-CoA dehydratase
- D-bifunctional protein, peroxisomal
- DBP
- hydroxysteroid (17-beta) dehydrogenase 4
- MFE-2
- MPF-2
- multifunctional protein 2
- peroxisomal multifunctional enzyme type 2
- peroxisomal multifunctional protein 2
- PRLTS1
- SDR8C1
- short chain dehydrogenase/reductase family 8C, member 1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Ferdinandusse S, Denis S, Mooyer PA, Dekker C, Duran M, Soorani-Lunsing RJ, Boltshauser E, Macaya A, Gartner J, Majoie CB, Barth PG, Wanders RJ, Poll-The BT. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ann Neurol. 2006 Jan;59(1):92-104. doi: 10.1002/ana.20702. Citation on PubMed
- Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am J Hum Genet. 2006 Jan;78(1):112-24. doi: 10.1086/498880. Epub 2005 Nov 15. Citation on PubMed or Free article on PubMed Central
- McMillan HJ, Worthylake T, Schwartzentruber J, Gottlieb CC, Lawrence SE, Mackenzie A, Beaulieu CL, Mooyer PA; FORGE Canada Consortium; Wanders RJ, Majewski J, Bulman DE, Geraghty MT, Ferdinandusse S, Boycott KM. Specific combination of compound heterozygous mutations in 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis. 2012 Nov 22;7:90. doi: 10.1186/1750-1172-7-90. Citation on PubMed or Free article on PubMed Central
- Moller G, van Grunsven EG, Wanders RJ, Adamski J. Molecular basis of D-bifunctional protein deficiency. Mol Cell Endocrinol. 2001 Jan 22;171(1-2):61-70. doi: 10.1016/s0303-7207(00)00388-9. Citation on PubMed
- Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010 Aug 13;87(2):282-8. doi: 10.1016/j.ajhg.2010.07.007. Epub 2010 Jul 30. Citation on PubMed or Free article on PubMed Central
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