Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency

(A) Pedigree structure of families with cerebellar ataxia with hypergonadotropic hypogonadism. Affected individuals are represented by black symbols. DNA from individuals that was used in this study is indicated (*). Single nucleotide polymorphism arrays and linkage were performed on samples I-2, II-1, II-2 (family 1), and II-1 and II-2 (family 2); WES was performed on sample II-2 (family 2). (B) A schematic representation of HSD17B4 indicating the dehydrogenase, hydratase, and SCP2 domains. The position and type of all compound heterozygous mutations identified in the 8 families reported with juvenile peroxisomal D-bifunctional protein deficiency to date (table 2) are indicated. A = pedigree 1, B = pedigree 2, C = pedigree 3, and D–H correspond to families 4–8, respectively. (C) Immunoblot analysis with an HSD17B4-specific antibody (1:1000, HPA021479) identified a ∼80 kDa full length and ∼35 kDA processed dehydrogenase domain protein in control fibroblasts (C1 and C2) that was significantly reduced in extracts derived from affected individuals II-1 and II-2 (families 1 and 2). An antibody directed against β-actin confirmed equivalent protein loading. FB = fibroblast. FB = fibroblast.