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Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result ( P = 1.84 × 10 −8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.

Item does not contain fulltext Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.

It was recently reported that rs1541160 on chromosome 1q24.2 has a marked effect on survival of amyotrophic lateral sclerosis (ALS) patients by influencing KIFAP3 expression. The cohorts used in that study were collected from ALS specialty clinics. We attempted to replicate these findings in a population-based cohort of 504 Italian ALS patients. None of 140 SNPs genotyped within the KIFAP3 locus (including rs1541160) had an effect on survival (log-rank P value for rs1541160 = 0.47) or on gene expression in that region. These data illustrate the complexities associated with analyzing ALS phenotypes for association.

Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons. The onset of disease typically occurs in the fifth decade of life and progresses rapidly; death occurs for 75% of patients within 5 years. The only drug that is available to treat ALS is riluzole, which extends survival by just 2-3 months. Thus, new therapeutic directions are being sought to prolong the lifespan of ALS patients. Since the discovery of SOD1 as a genetic determinant of ALS in 1993, SOD1-models of ALS have been extensively employed for the development of ALS therapeutics. Novel genetic targets are now under investigation following the recent discoveries linking TDP-43, FUS/TLS, angiogenin, KIFAP3 and UNC13A to ALS. In this review, we present several of the genetic contributors to both sporadic and familial forms of ALS and discuss their potential as therapeutic targets for this devastating disease.