Expanding the phenotype and genotype spectra of PLIN4-associated myopathy with rimmed ubiquitin-positive autophagic vacuolation

Yang, Kang; Zeng, Yi-Heng; Qiu, Yu-Sen; Li, Feng; Chen, Hai-Zhu; Jin, Ming; Chen, Long; Zheng, Fuze; Ding, Yuan-Liang; Cao, Chun‐Yan; Lin, Min-Ting; Chen, Wan‐Jin; Wang, Zhiqiang; Wang, Ning

doi:10.1007/s00401-022-02422-7

Cited by 9 publications

(13 citation statements)

References 2 publications

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“…Perilipin‐4 is mostly expressed in adipose cells, the brain, and the skeletal and heart muscles 9,10 . We reported the predominantly proximal muscle weakness supported by clinical and muscle imaging consistent with another Chinese study, compared to distal myopathy in the Italian cohort 3,4 . Patient S also presented with respiratory dysfunction which has never been reported.…”

Section: Discussionsupporting

confidence: 85%

“…We proposed that the subsarcolemmal p62/perilipin4 positivity is related to protein physiological distribution because perilipin‐4 is mainly located in the subsarcolemmal region 14 . Previous studies demonstrated that repeat expansion is associated with increased perilipin‐4 aggrephagy 3,4 . We observed overexpression of inflammatory markers and clustered mitochondria on muscle biopsy in all PLIN4 ‐associated patients, suggesting secondary muscle inflammation 15 …”

Section: Discussionmentioning

confidence: 59%

“…Whole‐exome sequencing of F‐II7, F‐III3, and Patient S in 2019 revealed negative results. Noting that the distinctive p62/ubiquitin‐positive staining pattern was the same as that in PLIN4 ‐associated myopathy published in 2020, we re‐analyzed PLIN4 using next‐generation sequencing (NGS), and its Integrative Genomics Viewer (IGV) visualization revealed an unusually high coverage in exon 3 3,4 . Polymerase chain reaction (PCR) amplification of this region showed a wild‐type band in unaffected relatives and a second ~1000 bp higher band in patients.…”

Section: Methods and Resultsmentioning

confidence: 72%

“…Identical pathological characteristics include ubiquitin-positive rimmed vacuoles (RVs) and increased perilipin-4/p62/FK2 positivity in both subsarcolemmal regions and vacuoles. [2][3][4] Here, we report one more family and the first sporadic patient with PLIN4-associated adult-onset limb-girdle weakness. Additionally, we found subsarcolemmal filamentous materials and membrane-bound granulofilamentous inclusions between myofibrils formed by proteinlipid deposits under electron microscopy (EM), which might be related to the pathogenesis of the 99 bp repeat expansion of PLIN4.…”

Section: Introductionmentioning

confidence: 84%

“…Recently, two studies reported an autosomal dominant myopathy with rimmed ubiquitin‐positive autophagic vacuolation associated with the coding 99 bp repeat expansion in PLIN4 , presenting with either distal myopathy or predominantly proximal muscle weakness. Identical pathological characteristics include ubiquitin‐positive rimmed vacuoles (RVs) and increased perilipin‐4/p62/FK2 positivity in both subsarcolemmal regions and vacuoles 2–4 …”

Section: Introductionmentioning

confidence: 99%

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Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4‐myopathy

Wang

Zhang

et al. 2022

Ann Clin Transl Neurol

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PLIN4-myopathy is a recently identified autosomal dominant muscular disorder caused by the coding 99 bp repeat expansion in PLIN4, presenting with distal or proximal weakness. Here, we report one family and one sporadic case of adult-onset PLIN4-associated limb-girdle weakness, whose diagnoses were achieved by a comprehensive genetic analysis workup. We provided additional evidence that the combination of subsarcolemmal/cytoplasmic ubiquitin/p62 positive deposits and rimmed vacuoles could serve as a strong indicator of PLIN4-myopathy. Moreover, we found novel myopathological features that were ultrastructural subsarcolemmal filamentous materials and membranebound granulofilamentous inclusions formed by the co-deposition of disrupted lipid droplets and p62 protein aggregates.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 59%

Section: Methods and Resultsmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4‐myopathy

Wang

Zhang

et al. 2022

Ann Clin Transl Neurol

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Molecular mechanisms of perilipin protein function in lipid droplet metabolism

Griseti,

Bello,

Bieth

et al. 2024

FEBS Letters

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Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino‐terminal PAT domain and an 11‐mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy‐terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.

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PLIN4-related myopathy: clinical, histological and imaging data in a large cohort of patients

et al. 2023

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Expanding the phenotype and genotype spectra of PLIN4-associated myopathy with rimmed ubiquitin-positive autophagic vacuolation

Cited by 9 publications

References 2 publications

Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4‐myopathy

Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4‐myopathy

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

PLIN4-related myopathy: clinical, histological and imaging data in a large cohort of patients

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