Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder

Mohammed, Mohammed; Al‐Hashmi, Nadia; Al-Rashdi, Samiya; Al-Sukaiti, Nashat; Al-Adawi, Kawther; Al-Riyami, Marwa; Al‐Maawali, Almundher

doi:10.1016/j.ejmg.2018.11.017

Cited by 31 publications

(53 citation statements)

References 19 publications

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“…The protein products of the HPS genes assemble in four multisubunit complexes, each involved in distinct steps of membrane trafficking and/or component sorting required for LRO biogenesis (Table 1; Bowman et al, 2019; Dell'Angelica, 2004; Huizing et al, 2008). The adaptor protein‐3 (AP‐3) complex consist of four subunits and includes the protein products of AP3B1 , which is mutated in HPS‐2 (Dell'Angelica, Shotelersuk, Aguilar, Gahl, & Bonifacino, 1999), and AP3D1 , mutated in HPS‐10 (Ammann et al, 2016; Mohammed et al, 2018). Biogenesis of lysosome‐related organelles complex‐3 (BLOC‐3) consists of the HPS1 and HPS4 proteins (Martina, Moriyama, & Bonifacino, 2003), defective in disease subtypes HPS‐1 and HPS‐4, respectively (Oh et al, 1998; Suzuki et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…The onset of PF is in childhood in AP‐3 deficiency (Gochuico et al, 2012) and middle age (30–50 years) in BLOC‐3 deficiency (Huizing et al, 2000). AP‐3 related PF has not been described in patients with HPS‐10 (Ammann et al, 2017; Mohammed et al, 2018). There is no approved medical therapy for HPS PF.…”

Section: Introductionmentioning

confidence: 99%

“… j Next‐generation sequencing identified this rare AP3D1 frameshift variant c.1978delG homozygous in three siblings with seizures, developmental delay, albinism, and immunodeficiency. Twin girls died before 6 days of age and their brother died at age 2 years of pneumonia and sepsis (Mohammed et al, 2018). …”

Section: Introductionmentioning

confidence: 99%

“…Immunologic investigations excluded HLH in the subject (Ammann et al, 2016; Enders et al, 2006; Jessen et al, 2013). A homozygous AP3D1 pathogenic frameshift variant, c.1978delG (p.Ala660Argfs*54), was identified in three siblings with seizures, developmental delay, albinism, and immunodeficiency; twin girls died before 6 days of age and their brother died at age 2 years of pneumonia and sepsis (Mohammed et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Immunodeficiency and/or neutropenia occurs in AP‐3‐deficient HPS, resulting in susceptibility to infections (subtypes HPS‐2 and HPS‐10; Ammann et al, 2016; de Boer et al, 2017; Fontana et al, 2006; Huizing et al, 2002; Mohammed et al, 2018). No BLOC‐2 or BLOC‐3 deficient subjects are described with immunodeficiency, but it was reported in two unrelated individuals with HPS‐9 (Badolato et al, 2012; Okamura et al, 2018) and therefore needs consideration in future BLOC‐1 deficient individuals.…”

Section: Introductionmentioning

confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast

et al. 2019

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Polyphosphates (polyP) are long chains of inorganic phosphates that can be attached to lysine residues of target proteins as a non-enzymatic post-translational modification. This modification, termed polyphosphorylation, may be particularly prevalent in bacterial and fungal species that synthesize and store large quantities of polyP. In this study, we applied a proven screening strategy to evaluate the polyphosphorylation status of over 200 candidate targets in the budding yeast S. cerevisiae. We report 8 new polyphosphorylated proteins that interact genetically and physically with a previously identified network of targets implicated in ribosome biogenesis. The expanded target network includes vacuolar proteins Prb1 and Apl5, whose modification with polyP suggests a model for feedback regulation of polyP synthesis, while raising additional questions regarding the location of polyphosphorylation in vivo.. CC-BY 4.0 International license a certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under

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Bleeding risks for uncharacterized platelet function disorders

Brunet

Badin

Chong

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Background The bleeding risks for nonsyndromic platelet function disorders (PFDs) that impair aggregation responses and/or cause dense granule deficiency (DGD) are uncertain. Objectives Our goal was to quantify bleeding risks for a cohort of consecutive cases with uncharacterized PFD. Methods Sequential cases with uncharacterized PFDs that had reduced maximal aggregation (MA) with multiple agonists and/or nonsyndromic DGD were invited to participate along with additional family members to reduce bias. Index cases were further evaluated by exome sequencing, with analysis of RUNX1 ‐dependent genes for cases with RUNX1 sequence variants. Bleeding assessment tools were used to estimate bleeding scores, with bleeding risks estimated as odds ratios (ORs) relative to general population controls. Relationships between symptoms and laboratory findings were also explored. Results Participants with uncharacterized PFD (n = 37; 23 index cases) had impaired aggregation function (70%), nonsyndromic DGD (19%) or both (11%), unlike unaffected relatives. Probable pathogenic RUNX1 variants were found in 2 (9%) index cases/families, whereas others had PFD of unknown cause. Participants with PFD had increased bleeding scores compared to unaffected family members and general population controls, and increased risks for mucocutaneous (OR, 4‐207) and challenge‐related bleeding (OR, 12‐43), and for receiving transfusions for bleeding (OR, 100). Reduced MA with collagen was associated with wound healing problems and bruising, and more severe DGD was associated with surgical bleeding ( P < .04). Conclusions PFDs that impair MA and/or cause nonsyndromic DGD have significantly increased bleeding risks, and some symptoms are more common in those with more severe DGD or impaired collagen aggregation.

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Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder

Cited by 31 publications

References 19 publications

Hermansky–Pudlak syndrome: Mutation update

Hermansky–Pudlak syndrome: Mutation update

Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast

Bleeding risks for uncharacterized platelet function disorders

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