A homozygous AP3D1 missense variant in patients with sensorineural hearing loss as the leading manifestation.

Autor: Frohne A; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.; Center of Anatomy and Cell Biology, Department for Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria., Koenighofer M; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Cetin H; Department of Neurology, Medical University of Vienna, Vienna, Austria., Nieratschker M; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Liu DT; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Laccone F; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria., Neesen J; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria., Nemec SF; Department of Biomedical Imaging and Image-Guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria., Schwarz-Nemec U; Department of Biomedical Imaging and Image-Guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria., Schoefer C; Center of Anatomy and Cell Biology, Department for Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria., Avraham KB; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel., Frei K; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Grabmeier-Pfistershammer K; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Kratzer B; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Schmetterer K; Center of Translational Research, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Pickl WF; Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria., Parzefall T; Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. thomas.parzefall@meduniwien.ac.at.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2023 Aug; Vol. 142 (8), pp. 1077-1089. Date of Electronic Publication: 2022 Nov 29.
DOI: 10.1007/s00439-022-02506-0
Abstrakt: Loss-of-function variants in AP3D1 have been linked to Hermansky-Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein-protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice.
(© 2022. The Author(s).)
Databáze: MEDLINE
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