A novel homozygous mutation in ALS2 gene in four siblings with infantile-onset ascending hereditary spastic paralysis

Eker, Hatice Koçak; Ünlü, Süleyman Ersin; Al-Salmi, Fatema; Crosby, Andrew H.

doi:10.1016/j.ejmg.2014.03.006

Cited by 14 publications

(5 citation statements)

References 16 publications

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“…Its structure contains three GEF domains that regulate the activity of Rho, Rac1, and Rab5 GTPases. Beyond that Alsin shows a complex domain architecture with three to seven (various description in the literature) identified regulator of chromatin condensation (RCC)‐like domains located near the N‐terminus, a centrally located Dbl homology and pleckstrin homology (DH/PH) domain, eight membrane occupation and recognition nexus (MORN) domains related to membrane binding, and a vacuolar protein sorting 9 (VPS9) domain at the C‐terminus (Eker, Unlu, Al‐Salmi, & Crosby, 2014; Soares et al, 2009) (Figure 1a). The presence of these functional domains and findings of recent functional studies indicate multiple important subcellular functions for Alsin, including modulation of endosome and mitochondrial trafficking as well as endocytosis (Hadano et al, 2006; Hadano, Kunita, Otomo, Suzuki‐Utsunomiya, & Ikeda, 2007; Hsu, Spannl, Ferguson, Hyman, & Parton, 2018; Otomo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Sprute

Jergas

Ölmez

et al. 2020

American J of Med Genetics Pt A

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Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenileonset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.

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Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Sprute

Jergas

Ölmez

et al. 2020

American J of Med Genetics Pt A

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“…ALS2 is located on chromosome 2q33 contains 33 introns and 34 exons, and encodes two splice variant of alsin protein: a long form of 1657 amino acids and a short form of 396 amino acids ( 3 ). To date, 14 different mutations have been identified in the ALS2 gene in 24 ALS patients ( 4 ). In addition, a novel c.2761C > T mutation was found to cause hereditary spastic paraplegia (HSP) with bulbar involvement ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms

Gautam¹,

Jara²,

Sekerková

et al. 2016

Hum. Mol. Genet.

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Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.

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“…Besides, ALS2 (alsin Rho guanine nucleotide exchange factor) and SLC6A1 (solute carrier family 6 member 1), which were the most prominent proteins related to the majorty of top GO terms, could be valuable for the diagnosis and targeted therapy of psychiatry,. Many studies reported that common motor neuron diseases have a close relationship with mutations in ALS2, resulting in juvenile lateral sclerosis and infantile-onset ascending spastic paralysis (Sheerin et al 2014; Eker et al 2014). The neurotransmitter r-aminobutyric acid (GABA) transporter 1, encoded by SLC6A1 gene, was verified as the most prominent biomarker in neural signal transduction pathways (Berg and Geschwind 2012).…”

Section: Discussionmentioning

confidence: 99%

A new bioinformatic insight into the associated proteins in psychiatric disorders

et al. 2016

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BackgroundPsychiatric diseases severely affect the quality of patients’ lives and bring huge economic pressure to their families. Also, the great phenotypic variability among these patients makes it difficult to investigate the pathogenesis. Nowadays, bioinformatics is hopeful to be used as an effective tool for the diagnosis of psychiatric disorders, which can identify sensitive biomarkers and explore associated signaling pathways.MethodsIn this study, we performed an integrated bioinformatic analysis on 1945 mental-associated proteins including 91 secreted proteins and 593 membrane proteins, which were screened from the Universal Protein Resource (Uniport) database. Then the function and pathway enrichment analyses, ontological classification, and constructed PPI network were executed.ResultsOur present study revealed that the majority of mental proteins were closely related to metabolic processes and cellular processes. We also identified some significant molecular biomarkers in the progression of mental disorders, such as HRAS, ALS2, SLC6A1, SLC39A12, SIL1, IDUA, NEPH2 and XPO1. Furthermore, it was found that hub proteins, such as COMT, POMC, NPS and BDNF, might be the potential targets for mental disorders therapy. Finally, we demonstrated that psychiatric disorders may share the same signaling pathways with cancers, involving ESR1, BCL2 and MAPK3.ConclusionOur data are expected to contribute to explaining the possible mechanisms of psychiatric diseases and providing a useful reference for the diagnosis and therapy of them.

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A novel homozygous mutation in ALS2 gene in four siblings with infantile-onset ascending hereditary spastic paralysis

Cited by 14 publications

References 16 publications

Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Genotype–phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms

A new bioinformatic insight into the associated proteins in psychiatric disorders

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