Alternative titles; symbols
HGNC Approved Gene Symbol: KIF11
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:92,593,130-92,655,395 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development | 152950 | Autosomal dominant | 3 |
KIF11 is a plus-end directed homotetrameric microtubule motor that functions during mitosis in microtubule crosslinking, antiparallel microtubule sliding, and bipolar spindle formation. KIF11 also mediates association of ribosomes with microtubules and increases translational efficiency (summary by Bartoli et al., 2011).
Blangy et al. (1995) stated that the forces required for mitotic spindle assembly and chromosome segregation are generated by the dynamic instability of the microtubules and by the action of motor proteins related to dynein (600112) and kinesin. There is unambiguous evidence that both cytoplasmic dynein and several kinesin-related proteins play essential roles in spindle assembly and function. They described the Eg5 protein, initially identified in Xenopus laevis and shown to be a kinesin-related protein associated with the mitotic spindle. Blangy et al. (1995) isolated a human homolog of Xenopus Eg5 (KIF11). They found that microinjection of antibodies against human KIF11 blocked centrosome migration and caused HeLa cells to arrest in mitosis with monoastral microtubule arrays. Furthermore, they found that an evolutionarily conserved cdc2 phosphorylation site (threonine-927) in KIF11 was phosphorylated specifically during mitosis in HeLa cells and by p34(cdc2)/cyclin B (123836) in vivo.
By Western blot analysis, Birtel et al. (2017) demonstrated expression of Kif11 in the mouse neuronal retina and testis. Kif11 immunostaining in the mouse retina showed localization in the retinal pigment epithelium, the inner segment, and the ciliary region of the photoreceptor layer, and in the inner and outer plexiform layers where the synaptic contacts of retinal neurons are present. Double-staining for Kif11 and centrin-3 (CETN3; 602907), a molecular marker for centrioles, basal bodies, and the connecting cilia of photoreceptor cells, revealed colocalization of the proteins in the ciliary region of photoreceptor cells. High-resolution analysis of immunofluorescence double labeling and immunoelectron microscopy consistently demonstrated Kif11 localization at the adjacent daughter centriole, the basal body, and in the connecting cilium, but not the axoneme, of the photoreceptor cilium.
The kinesin-related proteins are involved in functions related to movements of organelles, microtubules, or chromosomes along microtubules. These functions include axonal transport, microtubule sliding during nuclear fusion or division, and chromosome disjunction during meiosis and early mitosis. The kinesins are tetramers composed of 2 heavy and 2 light chains. The N-terminal heavy chain sequences show similarity in all the kinesin-related proteins. The N-terminal part forms the motor domain, with the microtubule-binding region allowing the protein to slide along the microtubule. It also possesses an ATP-binding site allowing an ATPase activity that provides the energy required for the movement. The C-terminal heavy chain and the light chain (see 600025) sequences differ among various kinesin-related proteins. They are assumed to be the binding sites specific for the different molecules to be moved. Within 1 species the kinesin family may be composed of multiple genes, since in Drosophila over 30 sites of in situ hybridization were detected with degenerated probes and 11 members of the kinesin superfamily have been identified (summary by Stewart et al., 1991).
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF11 belongs to the kinesin-5 family.
Using a molecular probe in the analysis of an interspecific backcross between C57BL/6J and Mus spretus, Justice et al. (1992) mapped the gene encoding the heavy chain of kinesin to mouse chromosome 18.
Tihy et al. (1992) mapped the human kinesin-related gene to 10q24.1 by fluorescence in situ hybridization. TPL2 (191195) and KNS are 2 genes on chromosome 10 in the human and chromosome 18 in the mouse. Previously, mouse chromosome 18 genes had been found on either human 18 or human 5.
Hartz (2012) mapped the KIF11 gene to chromosome 10q23.33 based on an alignment of the KIF11 sequence (GenBank U37426) with the genomic sequence (GRCh37).
Kapitein et al. (2005) showed that the vertebrate kinesin-5 Eg5 drives the sliding of microtubules depending on their relative orientation. They found in controlled in vitro assays that Eg5 had the remarkable capability of simultaneously moving at approximately 20 nanometers per second towards the plus ends of each of the 2 microtubules it crosslinked. For antiparallel microtubules, this resulted in relative sliding at approximately 40 nanometers per second, comparable to spindle pole separation rates in vivo. Furthermore, they found that Eg5 can tether microtubule plus ends, suggesting an additional microtubule-binding mode for Eg5. Kapitein et al. (2005) concluded that their results demonstrated how members of the kinesin-5 family are likely to function in mitosis, pushing apart interpolar microtubules as well as recruiting microtubules into bundles that are subsequently polarized by relative sliding.
Using diverse human and mouse cell lines, Bartoli et al. (2011) found that EG5 was required for efficient protein translation. Pharmacologic inhibition or small interfering RNA-mediated knockdown of EG5 reduced protein synthesis by approximately 40%. Inhibition of EG5 ATPase activity in RPE1 cells resulted in accumulation of polysomes, delayed ribosomal half-transit times, and a decrease in the ratio of polysomes to 80S monosomes. Cell fractionation, immunoprecipitation, and Western blot analysis revealed that EG5 associated with 80S ribosomes, 40S and 60S subunits of dissociated ribosomes, and polysomes. EG5 was required for the association of 80S ribosomes with microtubules in in vitro microtubule-binding assays. Bartoli et al. (2011) concluded that EG5 is required to link ribosomes to microtubules and enhances the efficiency of translation.
In affected individuals from 15 unrelated families with microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for 14 different mutations in the KIF11 gene (see, e.g., 148760.0001-148760.0005) that segregated with disease in the families.
In 5 unrelated patients with MCLMR, Mirzaa et al. (2014) identified 5 different heterozygous de novo mutations in the KIF11 gene (see, e.g., 148760.0007 and 148760.0008).
In 5 patients with MCLMR, who were originally diagnosed with familial exudative vitreoretinopathy (FEVR; see EVR1, 133780) and who did not have mutations in any of the known FEVR genes, Robitaille et al. (2014) identified 4 different heterozygous mutations in the KIF11 gene (see, e.g., 148760.0009-148760.0010). The first mutation (E470X; 148760.0009) was found by whole-exome sequencing, and the others were found by Sanger sequencing. The authors noted that patients with MCLMR may have additional ocular features, including retinal detachment.
Hu et al. (2016) analyzed potential pathogenic variants in the KIF11 gene resulting from whole-exome sequencing in 814 Chinese probands with various eye diseases, including 34 diagnosed with FEVR. They identified 4 probands with FEVR who had heterozygous truncating variants in KIF11 (see, e.g., Q744X, 148760.0011). Three of the 4 probands were found to be microcephalic and the fourth had a small head (OFC -1.3 SDS); 1 had mental retardation, and none exhibited lymphedema.
In 142 probands diagnosed with FEVR, Li et al. (2016) analyzed 6 FEVR-associated genes and identified 7 probands with heterozygous mutations in the KIF11 gene. All 7 had advanced FEVR and 3 exhibited microcephaly. Five of the mutations occurred de novo; the remaining 2 families demonstrated variable expressivity and incomplete penetrance of the missense and frameshift mutations, respectively, with 1 heterozygous parent exhibiting only a mild clinical phenotype and the other carrier parent being unaffected.
Chauviere et al. (2008) found that, while E5 +/- mice were healthy, fertile, and indistinguishable from wildtype, homozygous knockout of Eg5 was embryonic lethal. Examination of Eg5 -/- embryos revealed death between morula and blastocyst stages. In culture, Eg5 -/- blastocysts failed to hatch, rapidly collapsed, and degenerated inside the zona pellucida. X-Gal staining of Eg5 +/- embryos revealed highest Eg5 expression at 9 to 10 days postcoitus, after which staining was restricted to proliferating tissues. In adults, staining was detected in testis only, with prominent staining at the round spermatid stage and throughout spermiogenesis, but not in spermatogonia and spermatocytes.
In 4 patients from 2 unrelated families with microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for a 1159C-T transition in exon 10 of the KIF11 gene, resulting in an arg387-to-ter (R387X) substitution. The mutation segregated with disease in the first family but was found to have arisen de novo in the second family; it was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls. The 2 patients from the first family had microcephaly without eye abnormalities, and both had congenital edema: the male patient had minimal edema and mild learning difficulties (LD), whereas the female patient had congenital bilateral lower limb edema, mild LD, and dysmorphic features. The 2 patients from the second family had microcephaly with eye abnormalities but without congenital edema; the female patient had chorioretinopathy and mild LD, whereas the male patient had hypermetropic astigmatism, chorioretinopathy, and moderate LD.
In a male and a female patient from a family with microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for a 2-bp deletion (1039delCT) in exon 9 of the KIF11 gene, predicted to cause a frameshift and premature termination codon. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls. Both patients had microcephaly. Whereas the male patient had only mild learning difficulties (LD) without lymphedema or eye abnormalities, the female patient, who had more severe microcephaly, had congenital bilateral lower limb edema and pleural effusions, hypermetropic astigmatism and chorioretinopathy, and LD.
In a male patient with microcephaly, bilateral chorioretinopathy, congenital bilateral lymphedema of the lower limbs, and mild learning difficulties (MCLMR; 152950), originally reported by Vasudevan et al. (2005), Ostergaard et al. (2012) identified heterozygosity for a de novo 2830C-T transition in exon 3 of the KIF11 gene, resulting in an arg944-to-cys (R944C) substitution at a highly conserved residue within the bimC box in the C-terminal tail. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls.
In 2 related patients who had microcephaly without impaired intellectual development but with variable presence of chorioretinopathy and lymphedema (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for a 1-bp deletion (1592delA) in exon 13 of the KIF11 gene, predicted to cause a frameshift and premature termination codon. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls. Neither patient had learning difficulties. Whereas the female patient exhibited only microcephaly, the male patient also had congenital bilateral lower limb edema, bilateral chorioretinopathy, atrial septal defect, and dysmorphic features.
In 3 sibs, their mother, and their maternal grandfather, who had microcephaly without eye abnormalities but with variable presence of congenital lymphedema and/or impaired intellectual development (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for a 2547+2T-C transition in intron 18 of the KIF11 gene, predicted to cause premature termination. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls. Two of the patients had mild lymphedema of the hands in addition to congenital bilateral lymphedema of the lower extremities.
In 2 related female patients with microcephaly and bilateral chorioretinopathy (MCLMR; 152950), Ostergaard et al. (2012) identified heterozygosity for a 704C-G transversion in exon 7 of the KIF11 gene, resulting in a ser235-to-cys (S235C) substitution at a highly conserved residue within the motor domain. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 250 controls. Neither patient had lymphedema, and only 1 of them had learning difficulties.
In an 8-year-old girl (LR05-145), born of nonconsanguineous Caucasian parents, with severe microcephaly, bilateral chorioretinopathy, and mild to moderate intellectual disability (MCLMR; 152950), Mirzaa et al. (2014) identified heterozygosity for a de novo 2-bp deletion (c.2300_2301delTT; NM_004523.3) in exon 28 of the KIF11 gene, resulting in a frameshift and premature termination (Phe767SerfsTer8). The mutation, which was found by Sanger sequencing, was not present in the dbSNP (build 137) or the Exome Sequencing Project (ESP6500) databases.
In a 13-year-old boy (LR07-144), born of nonconsanguineous Caucasian parents, with severe microcephaly, bilateral chorioretinopathy, and moderate to severe intellectual disability (MCLMR; 152950), Mirzaa et al. (2014) identified heterozygosity for a de novo mutation (c.790-1G-A) in the KIF11 gene that was predicted to abolish the splice donor site of exons 7-8. The mutation was not found in the dbSNP (build 137) or Exome Sequencing Project (ESP6500) databases. The boy also had transient neonatal lymphedema, bilateral optic nerve hypoplasia with atrophic changes, and nystagmus.
By whole-exome sequencing in 2 sibs with microcephaly and chorioretinopathy (MCLMR; 152950), Robitaille et al. (2014) identified a heterozygous glu470-to-ter (E470X) substitution in the KIF11 gene. The 8-year-old proband originally had a diagnosis of familial exudative vitreoretinopathy (FEVR; see 133780). He had been noted to have intermittent esotropia since age 1.5 years and had amblyopia that did not respond to patching or atropine treatment. Retinal abnormalities were first noted at age 3 years. His past medical history was significant for microcephaly. Chorioretinal atrophy without retinal detachment was present in both eyes. His 5.5-year-old sister had a history of eyes drifting in or out intermittently and had received patching and atropine treatment that was discontinued at age 2 years. She also was noted to have microcephaly. She had a unilateral retinal fold and bilateral areas of chorioretinopathy. There were no other sibs and no family history of a condition compatible with a diagnosis of FEVR or MCLMR. The mutation was absent in both parents, suggesting mosaicism in 1 of them.
By Sanger sequencing in a boy with microcephaly and exudative vitreoretinopathy (MCLMR; 152950), Robitaille et al. (2014) identified heterozygosity for an intronic mutation (c.790-1G-T) in the KIF11 gene. The boy's vision problems were noted soon after birth, at which time he received a diagnosis of familial exudative vitreoretinopathy (FEVR; see 133780). At age 2, his development appeared normal, but his head circumference was 5 SDS below the mean. On eye examination, he had a large-angle esotropia with leukocoria on the right side. At age 15 months, he was able to fix and follow objects with his left eye but had no light perception on the right side. The right eye had a complete retinal detachment with a cloudy cornea. The left fundus showed peripheral vitreous condensation with subretinal fibrosis inferiorly after prior treatment with cryotherapy and scleral buckle. There was no family history for the disorder, and the mutation was not found in either of the proband's parents or his sister, suggesting that it occurred de novo.
In 2 Chinese sisters with microcephaly and eye anomalies (MCLMR; 152950), who were initially diagnosed as having familial exudative vitreoretinopathy (FEVR; see 133780), Hu et al. (2016) identified heterozygosity for a c.2230C-T transition in the KIF11 gene, resulting in a gln744-to-ter (Q744X) substitution. The mutation was not detected in either of their unaffected parents by Sanger sequencing, but cloning sequencing demonstrated somatic mosaicism for the Q744X mutation in the mother. Eye findings in the sisters included corneal opacity, microcornea, and retinal detachment; neither was responsive to light or objects. Head circumferences were -5.9 and -6.4 SDS, respectively.
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