Alternative titles; symbols
HGNC Approved Gene Symbol: YIF1B
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:38,303,558-38,321,887 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Kaya-Barakat-Masson syndrome | 619125 | Autosomal recessive | 3 |
YIF1B belongs to the FinGER protein family and is involved in endoplasmic reticulum (ER)-to-Golgi trafficking (Graab et al., 2019).
Carrel et al. (2008) cloned Yif1b from a rat hippocampus cDNA library. Bioinformatic analysis predicted that the 311-amino acid rat protein localizes to the Golgi membrane, with 5 transmembrane segments clustered in its C-terminal moiety, a long hydrophilic N-terminal domain within the cytoplasm, and a short C terminus turned to the ER lumen. Yif1b is well conserved across species, sharing 28%, 76%, 76%, and 89% amino acid identity with its orthologs from yeast, Xenopus, mouse, and human, respectively. Northern blot analysis detected Yif1b expression in a wide range of rat tissues, with high abundance in brain. Western blot analysis confirmed that the expression pattern of Yif1b protein correlated with that of its transcripts in all tissues. In rat brain, Yif1b was expressed in serotoninergic neurons in the dorsal raphe nucleus.
Using immunofluorescence analysis of transfected HeLa cells and rat hippocampal neurons, Alterio et al. (2015) showed that rat Yif1b localized to a vesicular compartment that shuttled between the ER, the intermediate compartment, and the Golgi apparatus.
Gross (2020) mapped the YIF1B gene to chromosome 19q13.2 based on an alignment of the YIF1B sequence (GenBank BC014974) with the genomic sequence (GRCh38).
Using yeast 2-hybrid and pull-down assays, Carrel et al. (2008) demonstrated that rat Yif1b interacted directly with the C terminus of rat 5-Ht1ar (HTR1A; 109760). Immunofluorescence analysis revealed that Yif1b colocalized with 5-Ht1ar in vesicles of the intermediate compartment in transfected COS-7 and LLC-PK1 cells. Knockdown experiment showed that Yif1b mediated targeting of 5-Ht1ar to neuronal dendrites and that this targeting required direct interaction between the C terminus of 5-Ht1ar and Yif1b.
Alterio et al. (2015) found that knockdown of YIF1B in HeLa cells accelerated vesicular stomatitis virus G protein (VSVG) anterograde traffic without causing ER stress and without preventing its glycosylation process through the Golgi. Likewise, VSVG anterograde traffic was accelerated in hippocampal neurons from Yif1b -/- mice. However, YIF1B inhibition in HeLa cells did not influence retrograde traffic of the B fragment of Shiga toxin. Electron microscopy revealed that long-term depletion of Yif1b resulted in disorganized Golgi architecture in CA1 pyramidal hippocampal neurons.
By immunoprecipitation analysis in human cells, Graab et al. (2019) showed that the transmembrane domain of YIF1B interacted with the 4 N-terminal transmembrane helices of ABCB9 (605453), which are essential ABCB9 lysosomal targeting. Functional characterization revealed that YIF1B was involved in lysosomal targeting of ABCB9, but that it was not an essential factor.
In 6 patients from 5 unrelated families with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), AlMuhaizea et al. (2020) identified homozygous loss-of-function mutations in the YIF1B gene (619109.0001-609109.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families that could be studied. None were present in the gnomAD database. Functional studies of the variants were not performed, but all were predicted to result in a complete loss of protein function.
In 10 patients from 6 unrelated families with KABAMAS, Diaz et al. (2020) identified homozygous or compound heterozygous mutations in the YIF1B gene (see, e.g., 619109.0001, 619109.0003-619109.0006). The patients, who originated from various countries, including France, Saudi Arabia, Iran, Canada, and Italy, were ascertained through the GeneMatcher database after whole-exome sequencing identified biallelic YIF1B mutations. All mutations were splice site, nonsense, or frameshift, except for 1 missense mutation (619109.0005) in 2 sibs in family 4, which was associated with a slightly less severe phenotype. Most mutations were predicted to lack all or most of the transmembrane domains, and Western blot analysis of some of the mutations showed absent or decreased YIF1B protein levels, consistent with a loss of function. Patient-derived fibroblasts showed reduced and shortened cilia compared to controls, suggesting ciliary anchoring defects (see ANIMAL MODEL). These findings, together with mouse studies, implicated several cellular processes that were disrupted by the YIF1B mutation, collectively resulting in a neurodevelopmental disorder.
Medico Salsench et al. (2021) described 8 new patients with KABAMAS due to biallelic mutations in the YIF1B gene and reviewed the literature on previously reported cases. Among the total of 24 patients from 19 families, 18 mutations (75%) were truncating or whole gene deletion mutations and 6 (25%) were missense mutations that changed highly conserved residues. All of the missense mutations were located in or close to the transmembrane domains and were not present in gnomAD, except for 1 which was found once in heterozygous state. Introduction of the missense mutations into a YIF1B expression plasmid did not result in significantly reduced YIF1B protein levels. The ability to meet limited developmental milestones (e.g., head control, independent sitting, limited speech) was seen only in patients with missense mutations, suggesting that residual YIF1B activity is present in these patients, consistent with in vitro data.
Diaz et al. (2020) found that knockdown of the Yif1b gene in mice did not cause ventilatory defects or increased susceptibility to seizures, although mutant mice showed impaired visual perception associated with retinal dysfunction and optic atrophy. Basal locomotion was normal, but there were some deficits in fine motor skills and coordination. Mutant mice had delayed cerebral myelination, enlarged ventricles, and cerebellar atrophy associated with a reduction in the number of Purkinje cells due to neurodegeneration and necrosis rather than apoptosis. There were disorganized dendritic trees and the presence of microglia cells. Electron microscopic studies of Purkinje cells showed abnormal fragmentation of the Golgi apparatus, large autophagosome-like vacuoles, and aberrant configuration of the ER with dilated cisterns compared to controls. Male Yif1b-null mice were infertile due to abnormal spermatozoa flagella which showed microtubule disorganization. Ciliary abnormalities were also observed in cerebellar Purkinje cells, hippocampal pyramidal cells, and fibroblasts. These findings, together with the human results, suggested that YIF1B is essential not only for Golgi and ER morphology and function, but also for primary ciliary integrity. Loss of YIF1B function leads to altered myelination, neuronal death, Golgi, ER, and ciliary defects with pathology related to disrupted trafficking of proteins, ultimately resulting in neurodevelopmental abnormalities.
In 4 female patients from 3 unrelated families of Arab descent (families 1, 2, and 3), with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), AlMuhaizea et al. (2020) identified a homozygous 1-bp duplication (c.186dupT, NM_001039872.2) in the YIF1B gene, resulting in a frameshift and premature termination (Ala64fs). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not present in the gnomAD database. Haplotype analysis suggested a founder effect. Functional studies of the variant were not performed, but the variant was predicted to result in a complete loss of protein function.
In 2 sisters, born of consanguineous Saudi Arabian parents (family 3), with KABAMAS, Diaz et al. (2020) identified a homozygous c.186dup mutation (c.186dup, NM_001039872.2) in the YIF1B gene, resulting in a frameshift and premature termination (Ala63CysfsTer18). The mutation, which was found by exome sequencing, was predicted to result in a loss of function. (In the article by Diaz et al. (2020), the protein change is cited as Ala63CysfsTer18 in table S1, but as Ala60CysfsTer18 in the text.)
In a boy, born of consanguineous parents (family 4), with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), AlMuhaizea et al. (2020) identified a homozygous 4-bp insertion (c.360_361insACAT, NM_001039672.3) in the YIF1B gene, resulting in a frameshift and premature termination (Gly121fs). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Segregation studies of the family were not possible. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 7-year-old girl, born of consanguineous Somali parents (family 5), with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), AlMuhaizea et al. (2020) identified a homozygous c.598G-T transversion (c.598G-T, NM_001039672.2) in the YIF1B gene, resulting in a glu200-to-ter (E200X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 2 brothers with KABAMAS from a Somali family, Diaz et al. (2020) identified homozygosity for the E200X mutation in the YIF1B gene. The mutation, which was identified by whole-exome sequencing, segregated with the disorder in the family.
In 2 brothers, born of French parents from the same village (family 2), with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), Diaz et al. (2020) identified a homozygous G-to-A transition (c.539+1G-A, NM_001039672.2) in intron 5 of the YIF1B gene, resulting in a splice site defect. The mutation was found by exome sequencing. Analysis of patient cells showed that the mutation resulted in the skipping of exon 5, causing a frameshift and premature termination (Ala161GlyfsTer18), which was predicted to result in a loss of function. Another patient with the disorder (family 5) carried the Ala161GlyfsTer18 mutation and a c.696-2A-C transversion (619109.0006) in the YIF1B gene on the other allele, resulting in a frameshift and premature termination (Met233PhefsTer40). These mutations segregated with the disorder in the family. Western blot analysis of patient cells showed absence of the full-length YIF1B protein.
In 2 adult sibs, born of consanguineous Iranian parents (family 4), with Kaya-Barakat-Masson syndrome (KABAMAS; 619125), Diaz et al. (2020) identified a homozygous c.367A-C transversion (c.367A-C, NM_001039672.2) in the YIF1B gene, resulting in a lys123-to-gln (K123Q) substitution at a highly conserved residue. The mutation was found by exome sequencing. Analysis of patient cells showed decreased YIF1B levels compared to controls, suggesting a loss of function, although functional studies were not performed. The patients had a slightly less severe phenotype with ability to walk in the first decade and some language achieved.
For discussion of the c.696-2A-C transversion (c.696-2A-C, NM_001039672.2) in the YIF1B gene, resulting in a frameshift and premature termination (Met233PhefsTer40), that was found in compound heterozygous state in a patient with Kaya-Barakat-Masson syndrome (KABAMAS; 619125) by Diaz et al. (2020), see 619109.0004.
AlMuhaizea, M., AlMass, R., AlHargan, A., AlBader, A., Salsench, E. M., Howaidi, J., Ihinger, J., Karachunski, P., Begtrup, A., Castell, M. S., Bauer, P., Bertoli-Avella, A., Kaya, I. H., AlSufayan, J., AlQuait, L., Chedrawi, A., Arold, S. T., Colak, D., Barakat, T. S., Kaya, N. Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy. Acta Neuropath 139: 791-794, 2020. [PubMed: 32006098] [Full Text: https://doi.org/10.1007/s00401-020-02128-8]
Alterio, J., Masson, J., Diaz, J., Chachlaki, K., Salman, H., Areias, J., Al Awabdh, S., Emerit, M. B., Darmon, M. Yif1B is involved in the anterograde traffic pathway and the Golgi architecture. Traffic 16: 978-993, 2015. [PubMed: 26077767] [Full Text: https://doi.org/10.1111/tra.12306]
Carrel, D., Masson, J., Al Awabdh, S., Borg Capra, C., Lenkei, Z., Hamon, M., Emerit, M. B., Darmon, M. Targeting of the 5-HT-1A serotonin receptor to neuronal dendrites is mediated by Yif1B. J. Neurosci. 28: 8063-8073, 2008. [PubMed: 18685031] [Full Text: https://doi.org/10.1523/JNEUROSCI.4487-07.2008]
Diaz, J., Gerard, X., Emerit, M.-B., Areias, J., Geny, D., Degardin, J., Simonutti, M., Guerquin, M.-J., Collin, T., Viollet, C., Billard, J.-M., Metin, C., and 23 others. YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations. Brain 143: 2911-2928, 2020. Note: Erratum: Brain 144: e40, 2021. [PubMed: 33103737] [Full Text: https://doi.org/10.1093/brain/awaa235]
Graab, P., Bock, C., Weiss, K., Hirth, A., Koller, N., Braner, M., Jung, J., Loehr, F., Tampe, R., Behrends, C., Abele, R. Lysosomal targeting of the ABC transporter TAPL is determined by membrane-localized charged residues. J. Biol. Chem. 294: 7308-7323, 2019. [PubMed: 30877195] [Full Text: https://doi.org/10.1074/jbc.RA118.007071]
Gross, M. B. Personal Communication. Baltimore, Md. 11/24/2020.
Medico Salsench, E., Maroofian, R., Deng, R., Lanko, K., Nikoncuk, A., Perez, B., Sanchez-Lijarcio, O., Ibanez-Mico, S., Wojcik, A., Vargas, M., Abbas Al-Sannaa, N., Girgis, M. Y., and 24 others. Expanding the mutational landscape and clinical phenotype of the YIF1B related brain disorder. Brain 144: e85, 2021. [PubMed: 34373908] [Full Text: https://doi.org/10.1093/brain/awab297]