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Author

Bart Appelhof

Other affiliations: University of Amsterdam
Bio: Bart Appelhof is an academic researcher from Leiden University Medical Center. The author has contributed to research in topics: Pontocerebellar hypoplasia & Missense mutation. The author has an hindex of 3, co-authored 4 publications receiving 54 citations. Previous affiliations of Bart Appelhof include University of Amsterdam.

Papers
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Journal ArticleDOI
TL;DR: This study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.
Abstract: Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

37 citations

Journal ArticleDOI
TL;DR: A de novo missense mutation in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene is reported in a patient with severe pontocerebellar hypoplasia, which further expands the spectrum of ITPR1‐related ataxias.
Abstract: We report a de novo missense mutation (c.7649T>A) in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene in a patient with severe pontocerebellar hypoplasia. The mutation results in an amino acid substitution of a highly conserved isoleucine by asparagine (p. I2550N) in the transmembrane domain. Mutations and deletions of the ITPR1 gene are associated with several types of autosomal dominant spinocerebellar ataxia, varying in age of onset and severity. Patients have signs of cerebellar ataxia and at most, a mild cerebellar atrophy on MRI. In contrast, the patient we report here has profound cerebellar and pontine hypoplasia. Our finding therefore further expands the spectrum of ITPR1-related ataxias. © 2016 Wiley Periodicals, Inc.

27 citations

Journal ArticleDOI
TL;DR: The homozygous MINPP1 gene is presented as a novel autosomal recessive pontocerebellar hypoplasia gene and several studies support its role in stress induced apoptosis.
Abstract: Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.

13 citations

Journal ArticleDOI
TL;DR: These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232∗ and p.Leu292∗ mutations and demonstrate the utility of WES in cases with unclear diagnoses.
Abstract: We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, p.Arg232 (∗) , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, p.Leu292 (∗) , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232 (∗) and p.Leu292 (∗) mutations and demonstrate the utility of WES in cases with unclear diagnoses.

3 citations


Cited by
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Journal ArticleDOI
21 May 2018-Traffic
TL;DR: Recent studies that have begun to unravel the intricacies by which the retromer and associated molecules contribute to receptor trafficking and how deregulation at this sorting domain can contribute to disease or facilitate pathogen infection are highlighted.
Abstract: The tubular endolysosomal network is a quality control system that ensures the proper delivery of internalized receptors to specific subcellular destinations in order to maintain cellular homeostasis. Although retromer was originally described in yeast as a regulator of endosome-to-Golgi receptor recycling, mammalian retromer has emerged as a central player in endosome-to-plasma membrane recycling of a variety of receptors. Over the past decade, information regarding the mechanism by which retromer facilitates receptor trafficking has emerged, as has the identification of numerous retromer-associated molecules including the WASH complex, sorting nexins (SNXs) and TBC1d5. Moreover, the recent demonstration that several SNXs can directly interact with retromer cargo to facilitate endosome-to-Golgi retrieval has provided new insight into how these receptors are trafficked in cells. The mechanism by which SNX17 cargoes are recycled out of the endosomal system was demonstrated to involve a retromer-like complex termed the retriever, which is recruited to WASH positive endosomes through an interaction with the COMMD/CCDC22/CCDC93 (CCC) complex. Lastly, the mechanisms by which bacterial and viral pathogens highjack this complex sorting machinery in order to escape the endolysosomal system or remain hidden within the cells are beginning to emerge. In this review, we will highlight recent studies that have begun to unravel the intricacies by which the retromer and associated molecules contribute to receptor trafficking and how deregulation at this sorting domain can contribute to disease or facilitate pathogen infection.

126 citations

Journal ArticleDOI
TL;DR: The clinical, neuroradiological and genetic characteristics of the different PCH subtypes are described, the differential diagnosis is summarized, and the discovery of new pathways involved in PCH is still symptomatic.
Abstract: Pontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH. In this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype. Many new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.

95 citations

Journal ArticleDOI
19 Sep 2018-Neuron
TL;DR: The data reveal an unexpected function for a lysosome-related organelle as an important building block for presynaptic biogenesis in Drosophila larvae and mouse hippocampal neurons.

94 citations

Journal ArticleDOI
TL;DR: The major cellular trafficking pathways and associated molecular machineries are outlined and how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans are discussed.
Abstract: Membrane trafficking pathways are essential for the viability and growth of cells, and play a major role in the interaction of cells with their environment. In this At a Glance article and accompanying poster, we outline the major cellular trafficking pathways and discuss how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans. We also briefly discuss possible therapeutic approaches that may be used in the future treatment of trafficking-based disorders.

70 citations

Journal ArticleDOI
TL;DR: Advances have extended the range of processes, in which Rabs function, and revealed roles for Rabs and their GAPs in the regulation of autophagy, and the emerging relationship between the domain architectures of Rab GEFs and vesicle coat protein complexes linked with GTPases of the Sar, ARF and Arl families in animal cells is discussed.

60 citations