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Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder
- Source :
- American Journal of Human Genetics, American Journal of Human Genetics, 2022, 109 (8), pp.1549-1558. ⟨10.1016/j.ajhg.2022.06.010⟩, Am J Hum Genet
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [N(ε)-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A [eIF5A(Dhp)] and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder.
- Subjects :
- DHPS
10039 Institute of Medical Genetics
Lysine
[SDV]Life Sciences [q-bio]
deoxyhypusine hydroxylase
DOHH
Gene Expression
translation
610 Medicine & health
neurodevelopmental disorder
hypusine
Mixed Function Oxygenases
post
translational modification
Neurodevelopmental Disorders
Report
EIF5A1
Genetics
Humans
570 Life sciences
biology
eIF5A
microcephaly
Alleles
Genetics (clinical)
Subjects
Details
- ISSN :
- 00029297 and 15376605
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....f514769cd3c3a2da1fb0f6d398fd4208