Alternative titles; symbols
HGNC Approved Gene Symbol: KIFBP
SNOMEDCT: 717822006;
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:68,988,803-69,016,982 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Goldberg-Shprintzen megacolon syndrome | 609460 | Autosomal recessive | 3 |
The KIAA1279 gene encodes a ubiquitously expressed protein that interacts with microtubules (summary by Drevillon et al., 2013).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned KIAA1279. The deduced protein contains 632 amino acids. RT-PCR detected high expression in heart, brain, ovary, testis, spinal cord, and all specific brain regions examined. Moderate expression was detected in all other adult tissues examined, as well as in fetal liver and brain.
Brooks et al. (2005) reported that the KIAA1279 gene encodes a 621-amino acid protein that shares 89% sequence homology with the mouse homolog. The predicted protein contains 2 tetratricopeptide repeats. Northern blot analysis of adult and fetal tissues detected expression of a 2.4-kb transcript in all tissues except blood leukocytes. The transcript was present in different parts of the adult central nervous system, including cerebellum, cortex, medulla, spinal cord, occipital lobe, frontal lobe, temporal lobe, and putamen.
By in situ hybridization of zebrafish embryos, Alves et al. (2010) found that Kbp was ubiquitously and diffusely expressed in early development and later became enriched in the central and enteric nervous systems. Fluorescence-tagged Kbp was expressed in the cytoplasm of transfected N1E-115 mouse neuroblastoma cells, with enrichment at the Golgi apparatus.
Brooks et al. (2005) stated that the KIAA1279 gene contains 7 exons spanning 28 kb.
By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA1279 gene to chromosome 10.
Gross (2012) mapped the KIAA1279 gene to chromosome 10q22.1 based on an alignment of the KIAA1279 sequence (GenBank BC012180) with the genomic sequence (GRCh37).
By yeast 2-hybrid analysis of an embryonic mouse cDNA library, Alves et al. (2010) found that Kbp interacted with the microtubule-destabilizing protein Scg10 (STMN2; 600621), with tubulin alpha-7 (Tuba3b), and with the kinesins Kif5b (602809), Kif5c (604593), Kif7 (611254), Kif2c (604538), Kif3a (604683), and Kifc1 (603763). Sequencing revealed that Kbp interacted with kinesin motor domains. Coimmunoprecipitation analysis of transfected HEK293 cells and colocalization of Kbp and Scg10 in N1E-115 cells confirmed the interaction between Kbp and Scg10. Kbp did not appear to interact directly with microtubules. Knockdown of Kbp expression in rat PC12 cells inhibited NGF-beta (NGFB; 162030)-induced neurite outgrowth. Alves et al. (2010) concluded that KBP has an indirect role in regulating microtubule dynamics and neurite outgrowth via its interaction with SCG10.
In human fibroblasts, Drevillon et al. (2013) demonstrated that the KIAA1279 protein had a cytosolic distribution and did not localize to the mitochondria. The protein colocalized with and strongly interacted with the microtubule cytoskeleton. KIAA1279 also partially colocalized and interacted with F-actin. Knockdown of KIAA1279 by siRNA in a neuroblastoma cell line induced dendritic spine depletion, and overexpression of KIAA1279 caused an increase in dendritic spine length.
By homozygosity mapping in a large consanguineous Moroccan family with Goldberg-Shprintzen syndrome (GOSHS; 609460), which is characterized by microcephaly, mental retardation, facial dysmorphism, and Hirschsprung disease, Brooks et al. (2005) mapped the disorder to chromosome 10q21.3-q22.1. In affected members of this family, they identified homozygosity for an arg90-to-ter mutation (R90X; 609367.0001) in the KIAA1279 gene. All patients in this family had bilateral generalized polymicrogyria in addition to Hirschsprung disease, thus establishing the importance of KIAA1279 in both enteric and central nervous system development. In 4 affected members of a consanguineous British Pakistani family, Brooks et al. (2005) identified homozygosity for a glu84-to-ter mutation (E84X; 609367.0002) in the KIAA1279 gene.
In 5 patients from 3 unrelated consanguineous families with GOSHS, Drevillon et al. (2013) identified homozygous truncating mutations in the KIAA1279 gene (609367.0001; 609367.0003-609367.0004), consistent with a loss of function. The patients had microcephaly, dysmorphic facial features, delayed psychomotor development, Hirschsprung disease, and neuronal migration defects in the brain. In vitro cellular studies showed that KIAA1279 normally interacts with actin and microtubules, suggesting a role in neuronal development and migration.
In a consanguineous Moroccan family, Brooks et al. (2005) found that individuals with Goldberg-Shprintzen syndrome (GOSHS; 609460) were homozygous for a c.303C-T transition in exon 1 of the KIAA1279 gene, resulting in an arg90-to-ter (R90X) substitution and a shortened protein of 89 amino acids.
In a Moroccan boy with GOSHS, Drevillon et al. (2013) identified homozygosity for the R90X mutation. They stated that the mutation resulted from a c.268C-T transition in the KIAA1279 gene. The mutation was not found in SNP databases or in 200 control chromosomes. Studies of patient cells showed significantly decreased levels of mutant mRNA and protein, suggesting nonsense-mediated mRNA decay.
In a consanguineous British Pakistani family, Brooks et al. (2005) found that individuals with GOSHS (609460) were homozygous for a c.285G-T transversion in the KIAA1279 gene, resulting in a glu84-to-ter (E84X) substitution.
In 2 brothers, born of consanguineous French parents, with GOSHS (609460), Drevillon et al. (2013) identified a homozygous c.599C-A transversion in the KIAA1279 gene, resulting in a ser200-to-ter (S200X) substitution. The mutation was not found in SNP databases or in 200 control chromosomes. Studies of patient cells showed significantly decreased levels of mutant mRNA and protein, suggesting nonsense-mediated mRNA decay.
In 2 affected patients from a large consanguineous Iraqi family with GOSHS (609460), Drevillon et al. (2013) identified a homozygous 2-bp deletion (c.604_605delAG) in the KIAA1279 gene, resulting in a frameshift and premature termination (Arg202IlefsTer2). The mutation was not found in SNP databases or in 200 control chromosomes. Studies of patient cells showed significantly decreased levels of mutant mRNA and protein, suggesting nonsense-mediated mRNA decay.
In 2 fetuses, offspring of consanguineous Pakistani parents, with microcephaly and polymicrogyria, features reminiscent of GOSHS (609460), Valence et al. (2013) identified a homozygous deletion of exons 2 and 3 of the KIAA1279 gene, resulting in a frameshift and premature termination (Asn143fsTer1). The mutation, which was found by linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not found in 200 control chromosomes. In both patients, the disorder was ascertained by prenatal ultrasound findings of ventriculomegaly, microcephaly, abnormal cortical folding, hypoplastic brainstem, and hypoplastic corpus callosum. One fetus had dysmorphic facial features. Postmortem examination of 1 fetus excluded Hirschsprung disease; postmortem examination was not performed in the other fetus. The findings expanded the phenotypic spectrum associated with KIAA1279 mutations, and Valence et al. (2013) suggested that the presence of polymicrogyria, microcephaly, and hypoplastic corpus callosum should suggest the clinical diagnosis of GOSHS, even in the absence of other features of the disorder.
Alves, M. M., Burzynski, G., Delalande, J.-M., Osinga, J., van der Goot, A., Dolga, A. M., de Graaff, E., Brooks, A. S., Metzger, M., Eisel, U. L. M., Shepherd, I., Eggen, B. J. L., Hofstra, R. M. W. KBP interacts with SCG10, linking Goldberg-Shprintzen syndrome to microtubule dynamics and neuronal differentiation. Hum. Molec. Genet. 19: 3642-3651, 2010. [PubMed: 20621975] [Full Text: https://doi.org/10.1093/hmg/ddq280]
Brooks, A. S., Bertoli-Avella, A. M., Burzynski, G. M., Breedveld, G. J., Osinga, J., Boven, L. G., Hurst, J. A., Mancini, G. M. S., Lequin, M. H., de Coo, R. F., Matera, I., de Graaff, E., Meijers, C., Willems, P. J., Tibboel, D., Oostra, B. A., Hofstra, R. M. W. Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am. J. Hum. Genet. 77: 120-126, 2005. [PubMed: 15883926] [Full Text: https://doi.org/10.1086/431244]
Drevillon, L., Megarbane, A., Demeer, B., Matar, C., Benit, P., Briand-Suleau, A., Bodereau, V., Ghoumid, J., Nasser, M., Decrouy, X., Doco-Fenzy, M., Rustin, P., Gaillard, D., Goossens, M., Giurgea, I. KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome. Hum. Molec. Genet. 22: 2387-2399, 2013. [PubMed: 23427148] [Full Text: https://doi.org/10.1093/hmg/ddt083]
Gross, M. B. Personal Communication. Baltimore, Md. 5/5/2012.
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Valence, S., Poirier, K., Lebrun, N., Saillour, Y., Sonigo, P., Bessieres, B., Attie-Bitach, T., Benachi, A., Masson, C., Encha-Razavi, F., Chelly, J., Bahi-Buisson, N. Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria. Neurogenetics 14: 215-224, 2013. [PubMed: 24072599] [Full Text: https://doi.org/10.1007/s10048-013-0373-x]