Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome

Bitetto, Giacomo; Ronchi, Dario; Bonato, Sara; Pittaro, Alessandra; Compagnoni, Giacomo Monzio; Bordoni, Andreina; Salani, Sabrina; Frattini, Emanuele; Lopez, Gianluca; Cribiù, Fulvia Milena; Corti, Stefania; Comi, Giacomo Pietro; Bresolin, Nereo; Fonzo, Alessio Di

doi:10.1093/hmg/ddz236

Cited by 13 publications

(21 citation statements)

References 20 publications

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“…Clinical manifestations depend on the affected system. In our case there are no neurologic abnormalities, yet and the findings on MRI may be due to reduced cerebellum Purkinje cells which are likely to be seen in AS patients as demonstrated by Giacomo Bitetto et al [ 11 ]. These findings may indicate that our patient may subsequently develop ipsilateral limb Dysmetria, hypotonia, tremor, and ataxia if the involvement is exacerbated or extended to the Vermis; so that lifelong monitoring is needed as there is potential for developing other new manifestations, even decades after the initial diagnosis, as well the potential need for other interventions such as Heller myotomy in cases where cardias Stenosis persists.…”

Section: Discussionsupporting

confidence: 53%

A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report

Eid

Chreitah

Aljanati

et al. 2022

Annals of Medicine &Amp; Surgery

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Section: Discussionsupporting

confidence: 53%

A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report

Eid

Chreitah

Aljanati

et al. 2022

Annals of Medicine &Amp; Surgery

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“…The broad neurological manifestations of the disease occur later in the course of the disease and Allgrove syndrome patients show a wide variability (29). Neurodegeneration can affect spinal motoneurons, Purkinje cells, striatal neurons and the autonomic system and the precise molecular mechanisms leading to neuronal loss are still unclear (30). A recent functional study on central nervous system tissues and broblasts of a novel Allgrove syndrome patient (homozygous AAAS mutation c.464G>A; p.R155H) presenting with a motor neuron disease, cerebellar ataxia (accompanied by severe loss of motor neurons and Purkinje cells) and autonomic dysfunction revealed signi cant reduction in the perinuclear expression of p.R155H-mutant ALADIN in the patient's brain correlating with a signi cant reduction of the AAAS-1 transcript, while the AAAS-2 transcript was upregulated in broblasts (30).…”

Section: Discussionmentioning

confidence: 99%

Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases

Hentschel

Czech

Münchberg

et al. 2020

Preprint

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Background: The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods: Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach (DIA). In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results: To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions: our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.

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“…It normally localizes to the cytoplasmic face of the nuclear membrane, as part of the nuclear pore complex (NPC), which is involved in nucleocytoplasmic transport. Bitetto et al 71 explored the consequences of the homozygous AAAS pathogenic variation c.464G>A (p.R155H) in the central nervous system tissues and fibroblasts of a patient presenting motor neuron disease, cerebellar ataxia, and autonomic dysfunction. By neuropathological analyses, a significant reduction in the perinuclear expression of Aladin was demonstrated, associated with a severe loss of motor neurons and Purkinje cells.…”

Section: Abnormal Nerve Functionmentioning

confidence: 99%

Hypolacrimia and Alacrimia as Diagnostic Features for Genetic or Congenital Conditions

Willems

Wells

Coubes

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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As part of the lacrimal apparatus, the lacrimal gland participates in the maintenance of a healthy eye surface by producing the aqueous part of the tear film. Alacrimia and hypolacrimia, which are relatively rare during childhood or young adulthood, have their origin in a number of mechanisms which include agenesia, aplasia, hypoplasia, or incorrect maturation of the gland. Moreover, impaired innervation of the gland and/or the cornea and alterations of protein secretion pathways can lead to a defective tear film. In most conditions leading to alacrimia or hypolacrimia, however, the altered tear film is only one of numerous defects that arise and therefore is commonly disregarded. Here, we have systematically reviewed all of those genetic conditions or congenital disorders that have alacrimia or hypolacrimia as a feature. Where it is known, we describe the mechanism of the defect in question. It has been possible to clearly establish the physiopathology of only a minority of these conditions. As hypolacrimia and alacrimia are rare features, this review could be used as a tool in clinical genetics to perform a quick diagnosis, necessary for appropriate care and counseling.

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Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome

Cited by 13 publications

References 20 publications

A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report

A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report

Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases

Hypolacrimia and Alacrimia as Diagnostic Features for Genetic or Congenital Conditions

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