Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation

Mansouri, Mahmoud; Marklund, Linda; Gustavsson, Peter; Davey, Edward J.; Carlsson, Birgit; Larsson, Catharina; White, Iréne; Gustavson, Karl‐Henrik; Dahl, Niklas

doi:10.1038/sj.ejhg.5201445

Cited by 106 publications

(88 citation statements)

References 23 publications

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“…Palmitoylation of Huntingtin by HIP14 (DHHC17) plays a protective role in inhibiting aggregation of the Huntingtin protein (12). Mutations in DHHC9 and DHHC15 are associated with forms of X-linked mental retardation (13,14). Accordingly, understanding the structure, function, and mechanism of this large family of enzymes is of obvious interest.…”

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confidence: 99%

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Nadolski¹,

Linder

2009

Journal of Biological Chemistry

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Palmitoylation of the yeast vacuolar protein Vac8 is important for its role in membrane-mediated events such as vacuole fusion. It has been established both in vivo and in vitro that Vac8 is palmitoylated by the Asp-His-His-Cys (DHHC) protein Pfa3. However, the determinants of Vac8 critical for recognition by Pfa3 have yet to be elucidated. This is of particular importance because of the lack of a consensus sequence for palmitoylation. Here we show that Pfa3 was capable of palmitoylating each of the three N-terminal cysteines of Vac8 and that this reaction was most efficient when Vac8 is N-myristoylated. Additionally, when we analyzed the Src homology 4 (SH4) domain of Vac8 independent of the rest of the protein, palmitoylation by Pfa3 still occurred. However, the specificity of palmitoylation seen for the full-length protein was lost, and the SH4 domain was palmitoylated by all five of the yeast DHHC proteins tested. These data suggested that a region of the protein C-terminal to the SH4 domain was important for conferring specificity of palmitoylation. This was confirmed by use of a chimeric protein in which the SH4 domain of Vac8 was swapped for that of Meh1, another palmitoylated and N-myristoylated protein in yeast. In this case we saw specificity mimic that of wild type Vac8. Competition experiments revealed that the 11th armadillo repeat of Vac8 is an important element for recognition by Pfa3. This demonstrates that regions distant from the palmitoylated cysteines are important for recognition by DHHC proteins.S-Palmitoylation (hereafter referred to as palmitoylation) is a widespread post-translational modification in which the fatty acid palmitate (16:0) is attached to a cysteine residue via a thioester linkage. Palmitate can be released from a cysteine by hydrolysis of the thioester linkage; thus palmitoylation is a reversible modification. Numerous eukaryotic proteins are palmitoylated, and substrates include both peripheral and transmembrane domain proteins. The functional consequences of palmitoylation are diverse. Membrane association, protein stability, and protein trafficking are among the properties that can be modulated by the palmitoylation status of a protein (reviewed in 1, 2).The enzymes responsible for palmitoylation have only recently been identified. The first protein acyltransferases (PATs) 3 discovered were Erf2 and Akr1 in yeast, which palmitoylate Ras2 and Yck2, respectively (3, 4). Both Erf2 and Akr1 are transmembrane proteins with an Asp-His-(His/Tyr)-Cys (DHHC) motif embedded in a cysteine-rich domain (CRD). Homology with this domain has identified five additional DHHC proteins in Saccharomyces cerevisiae. These seven proteins account for the bulk of palmitoylating activity in the cell (5).To date 23 DHHC proteins have been identified in mammals (6). As the field has progressed DHHC proteins have been linked to the regulation of neurotransmission (7-9), nitric oxide release (10), and cell-cell contacts (11). Palmitoylation of Huntingtin by HIP14 (DHHC17) plays a protective role in ...

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confidence: 99%

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Nadolski¹,

Linder

2009

Journal of Biological Chemistry

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“…DHHC8 knockout mice have sexually dimorphic alterations in locomotor activity and prepulse inhibition (39), whereas DHHC-5-deficient mice exhibit impaired fear conditioning and are born at half the expected rate (40). Furthermore, polymorphisms in the human DHHC8 gene are implicated in schizophrenia (39), whereas human DHHC9 and 15 mutations are associated with X-linked mental retardation (41,42). Thus, despite partial in vitro substrate overlap, relatively specific substrate effects occur in single PAT knockouts.…”

Section: Discussionmentioning

confidence: 99%

Memory and synaptic deficits in Hip14/DHHC17 knockout mice

Milnerwood

Parsons

Young

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Palmitoylation of neurotransmitter receptors and associated scaffold proteins regulates their membrane association in a rapid, reversible, and activity-dependent fashion. This makes palmitoylation an attractive candidate as a key regulator of the fast, reversible, and activity-dependent insertion of synaptic proteins required during the induction and expression of long-term plasticity. Here we describe that the constitutive loss of huntingtin interacting protein 14 (Hip14, also known as DHHC17), a single member of the broad palmitoyl acyltransferase (PAT) family, produces marked alterations in synaptic function in varied brain regions and significantly impairs hippocampal memory and synaptic plasticity. The data presented suggest that, even though the substrate pool is overlapping for the 23 known PAT family members, the function of a single PAT has marked effects upon physiology and cognition. Moreover, an improved understanding of the role of PATs in synaptic modification and maintenance highlights a potential strategy for intervention against early cognitive impairments in neurodegenerative disease.almitoylation is a posttranslational protein modification increasingly recognized as an important regulator of neuronal development, synaptic function, and plasticity (1, 2). Palmitoyl acyltransferase (PAT) enzymes regulate membrane association of proteins by catalyzing the addition of the fatty acid palmitate to cysteines via thioester bonds. Palmitoylation is readily reversible, making it an attractive candidate for a regulator of the rapid synaptic protein trafficking required for synaptic transmission and plasticity. The growing list of palmitoylated neuronal substrates includes scaffolds, ion channels, and vesicle-associated proteins, and their palmitoylation status can have dramatic effects on function and/or localization within membranes. For example, synaptic activity dynamically regulates palmitoylation of postsynaptic density protein-95 (PSD-95), influencing its clustering at postsynaptic sites (3-5), whereas palmitoylation of NMDA-and AMPA-type glutamate receptor subunits regulates their insertion, removal, and stabilization in the postsynaptic membrane (6-9). The importance of this modification within the brain is highlighted by implication of palmitoylation deficits in a number of neurological diseases including Alzheimer's disease, schizophrenia, and Huntington disease (HD) (10).To date, 23 DHHC proteins have been identified in humans. The PAT HIP14 (DHHC17) is enriched in the brain and has a number of known synaptic substrates including PSD-95, GluA1/ 2, GAD-65, SNAP-25, and synaptotagmin I (11-13), suggesting roles in pre-and postsynaptic function. Indeed, Hip14 siRNA reduces PSD-95 clustering in hippocampal cultures (12), and Hip14 loss-of-function impairs neurotransmitter release in Drosophila (14). Interestingly, Hip14 function is impaired in HD (15, 16), suggesting that some synaptic deficits observed in this disease (17-23) may arise from hypopalmitoylation of Hip14 substrates. In support of th...

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“…We performed FISH analysis with chromosome 10 derived bacterial artificial chromosomes (BACs) obtained from RZPD-Germany. Refined mapping using mini FISH was performed essentially as previously described [Rauch et al, 2001;Mansouri et al, 2005]. Probes of approximately 6 kb were generated by long-range PCR from the BAC clones RP11-203B22 and RP11-550A9, with the Advantage 2 PCR enzyme systems (BD Biosciences, Franklin Lakes, NJ and Clontech, Mountain View, CA).…”

Section: Cytogenetic and Fish Studiesmentioning

confidence: 99%

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population

Entesarian

Carlsson

Mansouri

et al. 2009

American J of Med Genetics Pt A

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We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four nonrelated Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.

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Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation

Cited by 106 publications

References 23 publications

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Memory and synaptic deficits in Hip14/DHHC17 knockout mice

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population

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