The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association

Zach, Frank; Graßmann, Felix; Langmann, Thomas; Sorusch, Nasrin; Wolfrum, Uwe; Stöhr, Heidi

doi:10.1093/hmg/dds268

Cited by 57 publications

(80 citation statements)

References 44 publications

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“…Recent work indicates that FAM161A plays a role in microtubule stabilization by maintaining transport processes in photoreceptors as a component of the cilia-basal body complex along with cilia proteins lebercilin, CEP290, OFD1 and SDCCAG8. 13,14 …”

Section: Discussionmentioning

confidence: 99%

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Duncan

Biswas

Kozák

et al. 2014

Ophthalmic Genetics

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Background Characterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects. Materials and Methods Six members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. Results Analysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C>T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss. Conclusions Exome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

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Section: Discussionmentioning

confidence: 99%

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Duncan

Biswas

Kozák

et al. 2014

Ophthalmic Genetics

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“…Proband H45 harbors a nonsense mutation (p.Q302X) in FAM161A. Loss-of-function mutations in this gene are reported to cause autosomal recessive retinitis pigmentosa (36,37). Interestingly, HM is coupled with these diseases in patients (38).…”

Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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“…Tubulin that is post-translationally modified by acetylation in microtubules can be extremely stable. According to previous reports, acetylated microtubules can be measured as an indicator of the levels of stable microtubules 24,25 . We measured the acetylated microtubules in the cell lysates using an acetylated tubulin-specific antibody (Fig.…”

Section: Tekt4 Variations Were Enriched After Paclitaxel-based Nctmentioning

confidence: 99%

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Jiang

Peng

et al. 2014

Nat Commun

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Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in B10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

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The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association

Cited by 57 publications

References 44 publications

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

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