Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy

AlMuhaizea, Mohammed A.; Almass, Rawan; AlHargan, Aljouhra; Albader, Anoud; Salsench, Eva Medico; Howaidi, Jude; Ihinger, Jacie; Karachunski, Peter; Begtrup, Amber; Castell, Monica Segura; Bauer, Péter; Bertoli‐Avella, Aida M.; Kaya, Ibrahim; AlSufayan, Jumanah; AlQuait, Laila; Chedrawi, Aziza; Arold, Stefan T.; Çolak, Dilek; Barakat, Tahsin Stefan; Kaya, Namik

doi:10.1007/s00401-020-02128-8

Cited by 19 publications

(24 citation statements)

References 7 publications

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“…In patients 3.1 and 5.1, lack of visual evoked potential was observed even with flash stimulation suggesting retinal dysfunction. Likewise, the patient from family 5 of the recently published study on patients carrying YIF1B mutations also exhibited cortical blindness (AlMuhaizea et al, 2020). Hence, we further explored visual functions in the Yif1b-KO mice.…”

Section: Yif1b-ko Mice Have Deficits Similar To Those Observed In Patients Carrying Yif1b Mutationsmentioning

confidence: 95%

“…Its deletion in mouse neurons leads to GA disorganization (Alterio et al, 2015) and alteration of the dendritic targeting of a specific serotonergic receptor (Carrel et al, 2008). A recent study identified mutations in the YIF1B gene in patients displaying progressive encephalopathy with various degrees of mixed movement disorder, microcephaly and epilepsy (AlMuhaizea et al, 2020). In the current study, we also identified mutations of the YIF1B gene in six families comprising 10 affected patients with neurological deficits that could not be classified by clinicians as a specific pathology, but whose clinical manifestations were close to those observed in Golgipathies.…”

Section: Introductionmentioning

confidence: 99%

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YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Díaz

Gérard

Emerit

et al. 2020

Brain

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Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

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Section: Yif1b-ko Mice Have Deficits Similar To Those Observed In Patients Carrying Yif1b Mutationsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Díaz

Gérard

Emerit

et al. 2020

Brain

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“…We performed filtering steps on the WES as described previously 12,13,15‐17 . The analysis yielded a single most plausible candidate, a homozygous missense variant in TBCD (NM_005993.5: c.1712A > G, p.K571R) in family A. Sanger sequencing confirmed complete segregation of the variant within the family (Figure 1(A)).…”

Section: Resultsmentioning

confidence: 99%

“…The sequencing was performed on the Ion Proton™ System (Life Technologies), using Ion PI™ Sequencing 200 Kit v3 with the Ion PI™ Chip Kit v2 (Life Technologies). WES data was filtered and the candidate variants were confirmed by Sanger Sequencing 12,13 . Variants were tested for potential pathogenicity using various prediction algorithms tools 14 …”

Section: Methodsmentioning

confidence: 99%

Hematological findings associated with tubulin‐folding cofactors D‐related encephalopathy: Expanding the phenotype

Al-Bakheet

Tohary

Khan³

et al. 2021

Clinical Genetics

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The dysfunction of microtubules (α/β‐tubulin polymers) underlies a wide range of nervous system genetic abnormalities. Defects in TBCD, a tubulin‐folding cofactor, cause diseases highlighted with early‐onset encephalopathy with or without neurodegeneration, intellectual disability, seizures, microcephaly and tetraparaperesis. Utilizing various molecular methods, we describe nine patients from four unrelated families with two novel exon 18 variants in TBCD exhibiting the typical neurological phenotype of the disease. Interestingly, all the investigated patients had previously unreported hematological findings in the form of neutropenia and mild degree of anemia and thrombocytopenia. In addition to delineating the neurological phenotype in several patients with TBCD variants, our study stresses on the new association of neutropenia, in particular, with the disease.

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“…Although YIF1B is known to interact with the serotonin receptor, HTR1A, the identification of further binding partners and the full extent of its involvement in serotonin signaling requires further investigation. A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder [23]. Although serotonin has been linked to cancer, a role for YIF1B in tumorigenesis and cancer progression has not been previously established.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and immune regulating roles of YIF1B in Pan-Cancer: a potential target for both survival and therapy response evaluation

et al. 2020

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The neurotransmitter serotonin has emerged as a tumor growth factor and immune response regulator through complex signaling pathways. Yip1 Interacting Factor Homolog B (YIF1B) is a membrane protein involved in serotonin receptor membrane trafficking and signal transmission in neuropathy. Participation of YIF1B in serotonin-induced tumor growth and immune regulation has not been previously investigated. Data for analysis of YIF1B mRNA expression were downloaded from the website portals TCGA, GTEx, CCLE and ICGC, including clinical and mutational information. Survival analysis included the Kaplan-Meier method for calculation of the cumulative incidence of the survival event and the log rank method for comparison of survival curves between groups. Infiltration levels of immune cells were calculated and correlated with YIF1B expression using the Spearman correlation test to evaluate significance. Further correlation analyses between YIF1B expression and mutation indicators such as tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) were also examined by the Spearman test. YIF1B expression was elevated in most cancer types and this high expression was indicative of poor overall survival and death specific survival. In BRCA and LIHC, high YIF1B expression correlated with a poor disease-free interval, indicating a role in malignancy progression. There was a positive relationship between YIF1B expression and immune cell infiltration in several cancer types, and YIF1B also positively correlated with TMB, MSI, and methylation in some cancer types, linking its expression to possible evaluation of therapy response. The bioinformatic analyses have, therefore, established YIF1B as a good biomarker for prognostic and therapeutic evaluation.

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Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy

Abstract: N. (2020). Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy. Acta Neuropathologica.

Cited by 19 publications

References 7 publications

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Hematological findings associated with tubulin‐folding cofactors D‐related encephalopathy: Expanding the phenotype

Prognostic and immune regulating roles of YIF1B in Pan-Cancer: a potential target for both survival and therapy response evaluation

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