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Cited by 20Cellular transport and secretionGenomics and Rare DiseasesLysosomal Storage Disorders Research

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index; 23 of the 39 sources its claims cite were checked for support.

Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome

Open access
Otsuji, Shiomi, Nishio, Yosuke, Tsujita, Maki, Rio, Marlene, Huber, Céline, Antón-Plágaro, Carlos, Mizuno, Seiji, Kawano, Yoshihiko, Miyatake, Satoko, Simon, Marleen, van Binsbergen, Ellen, van Jaarsveld, Richard H, Matsumoto, Naomichi, Cormier-Daire, Valerie, J.Cullen, Peter, Saitoh, Shinji, Kato, Kohji·2023·Journal of Medical Genetics
DOI 10.1136/jmg-2022-108602PMC PMC10086474
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Abstract

Purpose: The Retriever subunit VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS. Methods: We report three new patients with biallelic VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology. Results.: In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients with CCDC22 and WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake. Conclusion: VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This study reports three new patients with biallelic VPS35L variants and expands VPS35L-associated Ritscher-Schinzel syndrome as a distinct, clinically diverse entity with novel hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia. Cellular analyses link VPS35L/Retriever dysfunction to reduced cell-surface LRP1 and LDLR and impaired LDL uptake, suggesting a mechanism for hypercholesterolaemia.

Key findings

  • Three new patients (Pt-2, Pt-3, Pt-4) had overlapping RSS features but diverse severity: Pt-4 showed profound intellectual disability, short stature −6.5 SD (table; abstract says −6 SD) and congenital glaucoma causing blindness, while Pt-2 and Pt-3 were milder with short stature −2.1 and −2.9 SD and mild developmental delay/intellectual disability.
  • Novel complications included hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia; hypogammaglobulinaemia, intestinal lymphangiectasia and proteinuria were not reported in patients with CCDC22 or WASHC5 variants. All three new patients had low serum IgG; Pt-2 had cryptococcal meningitis at 15 years with IgG below 200 mg/dL, and proteinuria was sustained in Pt-1B, Pt-2 and Pt-3.
  • VPS35L and VPS26C protein levels were significantly decreased in patient-derived LCLs, with VPS35L significantly lower in the more severely affected Pt-1B than in milder Pt-2 and Pt-3. Variants N996del, P876L, M1020FS and A919T disrupted VPS29 binding; A526_K550del decreased binding to both VPS26C and VPS29.
  • VPS35L knockout/knockdown in 3T3 cells decreased cell-surface LRP1 and LDLR and diminished DiI-LDL uptake; VPS35L interacted with LDLR. Serum analyses showed total cholesterylester 264 vs 205 mg/dL in Pt-1B and 191 vs 181 mg/dL in Pt-2, LDL-CE 57% higher in Pt-2, apoE 3.3- and 3.2-fold higher in Pt-1B and Pt-2, and elevated CETP mass.

Methods

  • Clinical genetic analysis: trio-whole exome sequencing in a local diagnostic laboratory; two unrelated patients (Pt-3 and Pt-4) recruited via GeneMatcher; three patients with biallelic VPS35L variants identified and compared clinically with CCDC22/WASHC5 cases.
  • Cellular and biochemical analyses: EBV-transformed lymphoblastoid cell lines from patients; lentiviral expression of VPS35L-GFP WT and variant proteins in VPS35L-KO H4 cells; immunoprecipitation and western blot; biotinylation to assess cell-surface LDLR/LRP1; DiI-LDL uptake in VPS35L-KO/KD 3T3 cells.
  • Serum lipid analyses: lipoprotein subfractions by HPLC (LipoSEARCH), apolipoprotein E by turbidimetric immunoassay, and CETP mass by ELISA.

Limitations

  • Stated: more cases are required to build a complete understanding of VPS35L-related disorders and to determine whether Retriever, CCC and WASH complex dysfunction produce distinct clinical manifestations; further study is needed to explain why Pt-2-derived cells express higher VPS35L despite similar mRNA and GFP-nanotrap results.
  • Evident: the study is a very small case series (three new patients plus previously reported siblings), limiting generalizability and genotype–phenotype correlation.
  • Evident: some clinical/biochemical data are not available or not described for all patients (e.g., Pt-4 is NA for proteinuria, dyslipidaemia, increased transaminases and hypogammaglobulinaemia in table 1), so complication frequencies and severity comparisons are incomplete.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/jmg-2022-108602

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

23 of 39 cited sources checked · 7 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The SNX17-Retriever-CCC-WASH sorting pathway controls the sorting and recycling of numerous cell surface proteins, including ITGB1 and LRP1.

    “The SNX17-Retriever-CCC-WASH sorting pathway controls the sorting and recycling of numerous cell surface proteins, including integrins, such as integrin β1 (ITGB1), and low-density lipoprotein receptor-related protein 1 (LRP1).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [4] source
    • cites [5] source
    • cites [6] source

      The Results and discussion report that SNX17 supports integrin β1 recycling and that LRP1 levels fall when SNX17 is depleted. They do not establish the named SNX17–Retriever–CCC–WASH pathway: Retriever and CCC are not identified, and the authors report that SNX17 did not precipitate WASH-complex members. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [7] source

      The introduction and interaction experiments identify SNX17 as a protein that binds the cytoplasmic tail of the LDL receptor, linking it to a receptor-trafficking question. They do not establish a SNX17–Retriever–CCC–WASH pathway or show that it controls recycling of ITGB1 or LRP1; the LDL receptor studied here is not LRP1. The discussion also says the authors could not distinguish SNX17’s role in cellular trafficking from their binding results. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    VPS35L-WT-GFP localises to endosomes as defined by colocalisation with the early endosomal marker EEA1.

    “As shown in our previous report,4 VPS35L-WT-GFP localised to endosomes as defined by colocalisation with the early endosomal marker EEA1”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] source

      The Results section on retriever localisation (page unavailable) reports that endogenous C16orf62 colocalised with other retriever components on SNX17-labelled endosomes. The paper also mentions GFP-tagged C16orf62, but the passages do not show that the GFP-tagged protein colocalised with EEA1; EEA1 appears in the Methods antibody list. Thus the endosomal-localisation finding is supported, but the specific VPS35L-WT-GFP/EEA1 observation is not established by our copy. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
  • Findingcitation

    The free cholesterol ratio decreased to 7%±1% in HDL subclasses due to higher LCAT activity.

    “the free cholesterol ratio decreased to 7%±1% in HDL subclasses due to the higher LCAT activity.20 27 28”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [20] source

      The Phospholipid and cholesterol composition table (p. 2) lists free-cholesterol amounts for HDL2 and HDL3, so the paper addresses that part of the claim. It does not report a decrease to 7%±1% or attribute such a decrease to higher LCAT activity; searches for that figure and LCAT found no supporting passage. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [27] Rajaram, 1985, Reactivity of human lipoproteins with purified lecithin: cholesterol acyltransferase during incubations in vitro, Biochim Biophys Acta source
    • cites [28] source

      The “LCAT in HDL metabolism” section explains that LCAT esterifies free cholesterol on HDL, supporting the proposed mechanism. It does not report a decrease to 7%±1% in HDL subclasses, so the numerical finding is not supported by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Depletion of genes in the SNX17-Retriever-CCC-WASH sorting and recycling pathway leads to a decrease in expression of cell surface proteins such as ITGB1 and LRP1.

    “As such, depletion of genes in this sorting and recycling pathway leads to a decrease in the expression of these cell surface proteins.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [4] source
    • cites [5] source
    • cites [6] source

      The Results and discussion (page not provided) report that SNX17 depletion reduced LRP1 and ITGB1 abundance and lowered ITGB1 surface expression. The paper does not establish the same effect for depletion of genes across the named SNX17–Retriever–CCC–WASH pathway; it reports that SNX17 did not precipitate WASH components. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [7] source

      The paper’s discussion (page unavailable) says the authors had not succeeded in significantly reducing endogenous SNX17 expression, so it reports no depletion experiment establishing a decrease in cell-surface proteins. The paper links SNX17 to LDL-receptor trafficking, but our copy does not address depletion of the SNX17–Retriever–CCC–WASH pathway or its effect on ITGB1 and LRP1 surface expression. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Findingown data

    The ratio of free cholesterol to CE between patients and the healthy control pool were not significantly different.

    “the ratio between patients and the healthy control pool were not significantly different”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 8
  • It may state two separate claims as one. 21
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    When HDL generation by ABCA1 transporters at hepatocytes is compromised, VLDL secretion is rapidly reversed due to elevated triacylglycerol biogeneration in the liver.

    “It is thought that when HDL generation by ABCA1 transporters at hepatocytes is compromised, VLDL secretion is rapidly reversed due to elevated triacylglycerol biogeneration in the liver.22–26”
    Quote in the paperNot a substantial claim5 of 5 sources checked
    • cites [22] Tsujita, 2017, Exposure to high glucose concentration decreases cell surface ABCA1 and HDL biogenesis in hepatocytes, J Atheroscler Thromb source

      The Introduction and Discussion (page unavailable) support the claim that hepatocyte surface ABCA1 enables HDL generation and that reduced surface ABCA1 impairs it. They do not say that compromised HDL generation rapidly reverses VLDL secretion or that increased hepatic triacylglycerol production causes such a change. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] source

      The Discussion (page unavailable) says hepatocyte ABCA1 deficiency reduces HDL formation but increases secretion of triglyceride-enriched VLDL—the opposite of VLDL secretion being reversed when ABCA1 is compromised. It reports reversal of elevated plasma VLDL triglycerides after ABCA1 expression was restored, not after it was compromised. The paper does report increased triglyceride synthesis and secretion in deficient primary hepatocytes, but does not establish the claim's stated causal sequence. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [24] source

      The paper reports that ABCA1 silencing reduced large nascent HDL formation and increased VLDL triglyceride secretion in rat hepatoma cells. It does not support a rapid reversal of VLDL secretion or attribute the change to increased liver triglyceride synthesis: the discussion states that cellular TG synthesis did not increase and instead proposes reduced PI3-kinase-mediated HDL signaling. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] source

      The Results section (‘VLDL Secretion Is Impaired in CTα-deficient Hepatocytes’; page unavailable) reports both diminished VLDL secretion and increased intracellular triacylglycerol in cells with impaired HDL-related lipid efflux. It does not say that increased triacylglycerol production rapidly reverses VLDL secretion: the Discussion says short-term restoration of phosphatidylcholine synthesis did not restore secretion and suggests that recovery may require an extended period. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [26] Tsujita, 2005, On the hepatic mechanism of HDL assembly by the ABCA1/apoA-I pathway, J Lipid Res source

      The Discussion reports that inactivating ABCA1 inhibits HDL production by hepatocytes. The Results do not establish the claimed rapid reversal of VLDL secretion or attribute it to increased hepatic triacylglycerol production; they report only an insignificant decrease in a VLDL–LDL fraction under a different comparison. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    RSS (3C syndrome) has a triad of clinical features including craniofacial features, cerebellar anomalies and cardiac defects.

    “also known as 3C syndrome due to its triad of clinical features including craniofacial features, cerebellar anomalies and cardiac defects.”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [8] Gjerulfsen, 2021, Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: should the minimal diagnostic criteria be revised?, Eur J Med Genet source
    • cites [9] source
    • cites [10] source

      The paper’s discussion of the IGOLD #586 family reports cardiac abnormalities and specific facial features, but does not identify the family as having RSS or 3C syndrome. Searches for RSS, 3C syndrome, and cerebellar anomalies found no passage establishing the claimed triad in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [11] source
    • cites [12] Assoum, 2020, Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature, Am J Med Genet A source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    CCDC22 and WASHC5 are responsible genes for Ritscher-Schinzel syndrome (RSS).

    “CCDC22 and WASHC5 are known as responsible genes for Ritscher-Schinzel syndrome (RSS, MIM220210 and MIM300963)”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [8] Gjerulfsen, 2021, Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: should the minimal diagnostic criteria be revised?, Eur J Med Genet source
    • cites [9] source
    • cites [10] source

      The paper’s main text describes CCDC22 as a candidate gene for syndromic X-linked intellectual disability, not as a known responsible gene for Ritscher-Schinzel syndrome. Searches for Ritscher-Schinzel syndrome, RSS, and WASHC5 found no passage in our copy addressing the claimed RSS gene associations. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [11] source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [12] Assoum, 2020, Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature, Am J Med Genet A source

  • Probably not a substantial claim.

    Premisecitation

    The CCC and WASH complexes act together to facilitate endosomal trafficking of LDLR.

    “Previous reports found the CCC and WASH complexes act together to facilitate endosomal trafficking of LDLR.17 30 31”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [17] source
    • cites [30] source
    • cites [31] Wijers, 2019, The hepatic wash complex is required for efficient plasma LDL and HDL cholesterol clearance, JCI Insight source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    WASHC4 is a causative gene for autosomal recessive intellectual disability (MIM615817).

    “WASHC4 has been reported as a causative gene for autosomal recessive intellectual disability (MIM615817)”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [8] Gjerulfsen, 2021, Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: should the minimal diagnostic criteria be revised?, Eur J Med Genet source
    • cites [9] source
    • cites [10] source

      The paper’s main text identifies CCDC22 as a candidate gene for X-linked intellectual disability, not WASHC4. Searches for WASHC4 and autosomal recessive intellectual disability found no passage addressing the claimed WASHC4 association or MIM615817; the paper’s focus on a different gene does not itself contradict the claim. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [11] source

      The Discussion says a variant in the WASH-complex component SWIP was shown to cause non-syndromic intellectual disability, and reference 21 describes SWIP as a candidate gene for autosomal recessive intellectual disability. Our copy does not identify SWIP as WASHC4 or give MIM615817, so it does not verify the claim’s specific gene name and identifier. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [12] Assoum, 2020, Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature, Am J Med Genet A source

  • It may state two separate claims as one.

    Premisecitation

    Retriever localises to endosomes and regulates sorting and recycling of internalised integral proteins back to the cell surface through association with accessory proteins including SNX17, the CCC complex, and the WASH complex.

    “Retriever localises to endosomes from where it regulates the sorting and recycling of internalised integral proteins back to the cell surface through association with accessory proteins that include the cargo adaptor sorting nexin 17 (SNX17), the CCC (CCDC93, CCDC22 and COMMD) complex and the WASH complex, a pentameric protein complex that includes WASHC4 and WASHC5 subunits.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • It may state two separate claims as one.

    Findingown data

    Total serum cholesteryl ester was substantially increased in patient-1B (264 vs 205 mg/dL in control pool) and moderately increased in patient-2 (191 vs 181 mg/dL).

    “Total serum CE was substantially increased in patient-1B (264 vs 205 mg/dL in control pool), and was moderately increased in patient-2 (191 vs 181 mg/dL).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingnone given

    Hypogammaglobulinaemia, intestinal lymphangiectasia, and proteinuria have not been reported in patients with CCDC22 and WASHC5 variants.

    “The latter two complications as well as proteinuria have not been reported in patients with CCDC22 and WASHC5 variants.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Among the new patients with VPS35L-associated RSS, one showed a severe phenotype and the other two were milder.

    “One patient showed a severe phenotype and the other two were milder.”
    • Also stated in: § Genetic analysis and clinical findings · plain
      “Among the three patients, patient-4 exhibited the most severe condition with profound intellectual disability, severe short stature (−6 SD) and congenital glaucoma resulting in blindness.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Patient-1B and patient-2 had 3.3 and 3.2 times more apoE than the control pool, respectively.

    “Patient-1B and patient-2 had 3.3 and 3.2 times more apoE than the control pool, respectively.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Patient-4's elder brother was affected by the same condition and died due to sepsis after cardiac surgery for a large ventricular septal defect.

    “His elder brother was affected by the same condition, but a genetic test was not performed, and he died due to sepsis after cardiac surgery for a large ventricular septal defect.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Patient-4's elder brother was affected by the same condition.

  • It may state two separate claims as one.

    Findingown data

    Patient-4 exhibited the most severe condition with profound intellectual disability, severe short stature (−6 SD) and congenital glaucoma resulting in blindness.

    “Among the three patients, patient-4 exhibited the most severe condition with profound intellectual disability, severe short stature (−6 SD) and congenital glaucoma resulting in blindness.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In patient-2, VLDL-CE was not influenced while LDL-CE was 57% higher than control pool serum.

    “In patient-2, VLDL-CE was not influenced while LDL-CE was 57% higher than control pool serum (figure 3C, D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    N996del and P876L variant proteins show disrupted binding to VPS29 while binding to VPS26C is not significantly affected.

    “The two novel variant proteins, N996del and P876L, showed results similar to that observed in A919T, with disrupted binding to VPS29 while binding to VPS26C was not significantly affected (figure 2E, F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Patient-2 and patient-3 showed milder phenotypes with short stature between −2 and −3 SD and mild developmental delay or intellectual disability.

    “Patient-2 and patient-3 showed milder phenotypes with short stature between −2 and −3 SD and mild developmental delay or intellectual disability.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    HDL-CE dropped to 38.6 mg/dL in patient-2, accompanied by 2.4 times more VLDL-TG and 3.1 times more LDL-TG compared with the control pool.

    “HDL-CE dropped to 38.6 mg/dL in patient-2, which was accompanied by 2.4 times more VLDL-TG and 3.1 times more LDL-TG compared with the control pool.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Proteinuria was identified in three patients with VPS35L pathogenic variants, which has not been reported in patients with 3C/RSS.

    “proteinuria was identified in three patients with VPS35L pathogenic variants, which has not been reported in patients with 3C/RSS.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Disruption of protein assembly in the Retriever complex is likely the cause of pathogenicity in these patients, leading to decreased protein stability and reduced efficiency of endosomal integral protein sorting.

    “these data suggest that disruption of protein assembly in the Retriever complex is likely to be the cause of pathogenicity, leading to decreased protein stability and a resultant reduction in the efficiency of endosomal integral protein sorting in cells established from these patients.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premiseown data

    Only one pair of siblings with VPS35L variants have been reported to date, and their condition was significantly more severe than typical RSS.

    “To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS.”
    • Also stated in: § Introduction · plain
      “That said, they exhibited a more severe disease condition compared with patients with RSS that had WASHC5 or CCDC22 pathogenic variants.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The A919T variant lacks binding to VPS29, resulting in protein instability.

    “as we previously reported that the A919T variant lacked binding to VPS29, resulting in protein instability”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Retriever is a stable protein complex composed of three subunits, VPS35L, VPS29 and VPS26C.

    “Retriever is a stable protein complex composed of three subunits, VPS35L, VPS29 and VPS26C.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

  • The quote only partly states this claim.

    Interpretationown data

    The splice site variant c.1650+2T>A caused an exon extension resulting in nonsense-mediated mRNA decay.

    “These results confirmed that the splice site variant caused an exon extension resulting in NMD (online supplemental figure S1D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity.

    “VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: More clinical information is required to better understand the clinical manifestations of VPS35L-associated RSS.

  • It may state two separate claims as one.

    Interpretationown data

    The c.3057del variant is located just before the last exon, enabling both alleles to escape from mRNA decay.

    “the other c.3057del variant was located just before the last exon, which enabled both alleles to escape from mRNA decay.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The previously reported siblings with VPS35L variants comprised an elder girl who died in the infantile period due to sudden cardiac arrest, and a younger boy who presented a variety of severe complications.

    “The previously reported siblings with VPS35L variants comprised an elder girl who died in the infantile period due to sudden cardiac arrest, and a younger boy who presented a variety of severe complications.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source

  • It may state two separate claims as one.

    Interpretationown data

    This report expands the clinical spectrum of patients with pathogenic VPS35L variants, and identifies both overlapping and distinctive features compared with patients with CCC and WASH complex dysfunction.

    “this report expands the clinical spectrum of patients with pathogenic VPS35L variants, and identifies both overlapping and distinctive features compared with patients with CCC and WASH complex dysfunction.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Depletion of VPS35L and loss of functional Retriever endosomal sorting complex leads to decreased cell surface expression of LDLR and LRP1, resulting in impairment of normal LDL uptake.

    “Our cellular analysis suggests that depletion of VPS35L, and loss of the functional Retriever endosomal sorting complex, leads to a decreased cell surface expression of LDLR and LRP1, resulting in impairment of normal LDL uptake.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    Prior to this study, only one pair of siblings with VPS35L pathogenic variants had been described, who presented with a severe form of congenital malformation syndrome.

    “Prior to this study, only one pair of siblings with VPS35L pathogenic variants had been described, who presented with a severe form of congenital malformation syndrome.”
    Quote in the paperNot a substantial claim
28 of 28

  • The paper relies on this without support.

    More clinical information is required to better understand the clinical manifestations of VPS35L-associated RSS.

    “To better understand the clinical manifestations of VPS35L-associated RSS, more clinical information is required.”

  • The paper relies on this without support.

    Impairment of cell surface protein recycling and the subsequent reduction of protein expression level is likely a molecular cause of the observed clinical phenotypes.

    “While impairment of cell surface protein recycling and the subsequent reduction of protein expression level is likely to be a molecular cause of the observed clinical phenotypes, the underlying molecular mechanisms in these patients have not been well investigated.”

  • The paper relies on this without support.

    Patient-4's elder brother was affected by the same condition.

    “His elder brother was affected by the same condition, but a genetic test was not performed”

  • The paper relies on this without support.

    It has not been determined whether the Retriever complex is required for recycling of LRP1 and LDLR.

    “However, it has not been determined if the Retriever complex is also required for recycling of these proteins.”

  • The paper relies on this without support.

    The Retriever complex interacts with the CCC and WASH complexes in the endosomal recycling network.

    “the Retriever complex interacts with the CCC and WASH complexes in the endosomal recycling network”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mutations in Commander subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS).

    “mutations in its subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS), a multi-system developmental disorder characterised by abnormal craniofacial features, cerebellar hypoplasia, and stunted cardiovascular development.7,8,9,10,11,12,13,14”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [11]

    The Introduction identifies CCDC22 as a gene responsible for Ritscher-Schinzel syndrome and describes the syndrome’s craniofacial, cerebellar and cardiac features. The References include a study titled “Missense variant in CCDC22 causes X-linked recessive intellectual disability,” but the paper’s main text does not directly make the XLID claim; its explicit discussion of intellectual disability here concerns an autosomal recessive condition linked to WASHC4. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • Evidence that CCDC22(T17A), CCDC22(Y557C), and VPS35L(A830T) perturb endosomal recycling of LRP1 and LDLR and lead to hypercholesterolemia.

    “Taken alongside evidence that CCDC22(T17A), CCDC22(Y557C), and VPS35L(A830T) perturb endosomal recycling of LRP1 and LDLR and lead to hypercholesterolemia,11,65”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [11]

    The Results section (‘VPS35L is essential for lipid metabolism’; page unavailable) reports that VPS35L depletion reduced cell-surface LRP1 and LDLR and impaired LDL uptake. The Discussion links this mechanism to hypercholesterolaemia in patients with VPS35L-associated RSS. Our copy does not establish these effects for the specified VPS35L(A830T) variant or for CCDC22(T17A) and CCDC22(Y557C). (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans, thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling.

    “It is worth noting that mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling, a phenotype also seen in mouse models of liver deficiency of Ccdc22, Vps35l and Commd1 [5, 7, 30–32].”

    From CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome (2025) · cites this paper as [7]

    The Results report hypercholesterolaemia in patients with VPS35L variants and show that VPS35L depletion reduces cell-surface LDL receptors and LDL uptake. The Discussion says the CCC and WASH complexes facilitate lipoprotein-receptor trafficking, but our copy does not establish that CCDC22 and WASHC5 variants also cause hypercholesterolaemia in humans through this mechanism. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders.

    “SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders [111-114, 148-150].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [150]

    The Introduction (page not provided) describes SNX17 as an adaptor associated with Retriever and the CCC complex in a shared sorting pathway. It also links genes in that pathway to intellectual disability and Ritscher-Schinzel syndrome with developmental delay. Our copy does not identify the larger assembly as “Commander” or state that SNX17-Retriever assembles into it. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Mutations associated with Ritscher-Schinzel syndrome cause a decrease in the levels of Retriever subunits or CCC subunits, which interferes with the normal function of these complexes.

    “several mutations associated with Ritscher-Schinzel syndrome cause a decrease in the levels of Retriever subunits (Otsuji et al., 2022; Kato et al., 2020) or CCC subunits (Starokadomskyy et al., 2013), which interferes with the normal function of these complexes.”

    From Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity (2023) · cites this paper as Otsuji et al., 2022

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Patient-4's hypogammaglobulinaemia is reported but marked unavailable in Table 1

    Minor

    The results state that all three new patients, including patient-4, had low serum IgG. Table 1 instead marks hypogammaglobulinaemia for patient-4 as NA, which the table defines as information not available.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Okazaki, 1987, Investigation of apolipoproteins using Hitachi 7150, Japanese Journal of Clinical Laboratory Automation, 12

Cited by

Sorted by citations

Related

Metadata

Authors
Otsuji, S., Nishio, Y., Tsujita, M., Rio, M., Huber, C., Antón-Plágaro, C., Mizuno, S., Kawano, Y., Miyatake, S., Simon, M., van Binsbergen, E., van Jaarsveld, R. H., Matsumoto, N., Cormier-Daire, V., J.Cullen, P., Saitoh, S., & Kato, K.
Affiliations
  • Nagoya City University (JP)
  • Université Paris Cité, Génétique clinique, INSERM UMR 1163, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France
  • Hôpital Necker-Enfants Malades (FR)
  • University of Bristol (GB)
  • Aichi Developmental Disability Center (JP)
  • Toyota Memorial Hospital (JP)
  • Yokohama City University Hospital (JP)
  • University Medical Center Utrecht (NL)
  • Yokohama City University (JP)
  • School of Biochemistry, Faculty of Life Sciences, University of Bristol, Bristol, UK
Corresponding author
Kato, Kohji
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2022-09-16
Volume
60
Issue
4
Pages
359-367
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmg-2022-108602
PMC
PMC10086474
OpenAlex
W4296076718
Cited by
19
References
30
Citations by year
2026: 2 · 2025: 7 · 2024: 3 · 2023: 7
FWCI
1.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Medical Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
Funders
  • the Medical Research Council (MR/L007363/1, MR/P018807/1)
  • Lister Institute of Preventive Medicine
  • Japan Intractable Diseases (Nanbyo) Research Foundation
  • Japanese Agency for Medical Research and Development, AMED (JP21ek0109486, JP21ek0109493, JP21ek0109549)
  • Royal Society Noreen Murray Research Professorship (RSRP/R1/211004)
  • JSPS KAKENHI (JP19K23823, JP20H05700, JP20K07907, JP20K16897, JP20K21583)
  • Wellcome Trust (220260/Z/20/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
Keywords
biallelic variants, hypercholesterolemia, hypogammaglobulinemia, intestinal lymphangiectasia, proteinuria, LDL receptor, LDL uptake, clinical phenotype variability
MeSH terms
Abnormalities, Multiple, Dandy-Walker Syndrome, Heart Septal Defects, Atrial, Humans, Hypercholesterolemia, Craniofacial Abnormalities, Vesicular Transport Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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