ArticlePLoS genetics2012
Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 66 citations in OpenAlex.
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- Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- PRKCI Mediates RadiosensitivityFrontiers in oncology · 2022Article
- Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.American journal of medical genetics. Part A · 2021Article
- Human Adult Fibroblast-like Synoviocytes and Articular Chondrocytes Exhibit Prominent Overlap in Their Transcriptomic Signatures.ACR open rheumatology · 2021Article
- Palmitoylation of Hedgehog proteins by Hedgehog acyltransferase: roles in signalling and disease.Open biology · 2021Review
- Congenital Malformations in Sea Turtles: Puzzling Interplay between Genes and Environment.Animals : an open access journal from MDPI · 2021Review
- Genetics and signaling mechanisms of orofacial clefts.Birth defects research · 2020Review
- Identification of novel candidate pathogenic genes in pituitary stalk interruption syndrome by whole-exome sequencing.Journal of cellular and molecular medicine · 2020Article
- Neurogenesis From Neural Crest Cells: Molecular Mechanisms in the Formation of Cranial Nerves and Ganglia.Frontiers in cell and developmental biology · 2020Review
- Locating and Characterizing a Transgene Integration Site by Nanopore Sequencing.G3 (Bethesda, Md.) · 2019Article
- Hedgehog Signaling and Embryonic Craniofacial Disorders.Journal of developmental biology · 2019Review
- Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis.Genome research · 2019Article
- Hedgehog Signal and Genetic Disorders.Frontiers in genetics · 2019Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain. Mutations in SHH underlie most familial (17%) cases of HPE; and, consistent with this, Shh is expressed in midline embryonic cells and tissues and their derivatives that are affected in HPE. It has long been recognized that a graded series of facial anomalies occurs within the clinical spectrum of HPE, as HPE is often found in patients together with other malformations such as acrania, anencephaly, and agnathia. However, it is not known if these phenotypes arise through a common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severe condition observed in humans. Hhat is required for post-translational palmitoylation of Hedgehog (Hh) proteins; and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defects in cartilage and bone differentiation. Therefore our work shows that Hhat loss-of-function underscrores HPE; but more importantly it provides a mechanism for the co-occurrence of acrania, holoprosencephaly, and agnathia. Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders.
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