Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation

Kurashige, Takashi; Morino, Hiroyuki; Matsuda, Yukiko; Mukai, Tomoya; Murao, Tomomi; Toko, Megumi; Kume, Kodai; Ohsawa, Ryosuke; Torii, Tsuyoshi; Tokinobu, Hiroshi; Makino, Hírofumi; Kawakami, Hideshi

doi:10.1136/jnnp-2019-321279

Cited by 9 publications

(6 citation statements)

References 5 publications

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“…Functional experiments showed that this variant could lead to reduction of protein expression and localization of proteins in cells ( 16 ). Recently, homozygous variant Y107H was found in two patients with RP and ALS ( 33 ). Y107C, tyrosine changed into cysteine at position 107, has been also reported to cause isolated RP or CORD in homozygous patients ( 12 , 16 ).…”

Section: Resultsmentioning

confidence: 99%

Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma

Yang,

Li,

Yang

et al. 2023

Front. Med.

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BackgroundCone-rod dystrophy (CORD) caused by pathogenic variants in CFAP410 is a very rare disease. The mechanisms by which the variants caused the disease remained largely unknown. CFAP410 pathogenic variants were identified in a cone-rod dystrophy with macular staphyloma patient. We explored the pathogenicity and performed functional analysis of two compound heterozygous mutations.MethodsA 6-year-old boy complained decreased vision for 1 year, underwent ocular examinations together with systemic X-ray check. Blood sample was taken for targeted next generation sequencing (Tg-NGS). Pathogenicity of identified variants was determined by ACMG guideline. Mutated plasmids were constructed and transferred to HEK293T cells. Cell cycle, protein stability, and protein ubiquitination level was measured.ResultsThe best-corrected visual acuity of proband was 0.20 bilaterally. Fundus showed macular staphyloma and uneven granular pigment disorder in the periphery of the retina. SS-OCT showed thinning and atrophy of the outer retina, residual ellipsoid zone (EZ) in the fovea. Scotopic and photopic ERG responses severe reduced. Two heterozygous missense pathogenic variants, c.319 T > C (p.Tyr107His) and c.347 C > T (p.Pro116Leu) in exon 4 of the CFAP410, were found and were pathogenic by the ACMG guideline. In vitro, pathogenic variants affect cell cycle. Immunofluorescence and western blotting showed that the mutant proteins decreased expression levels protein stability. Meanwhile, co-IP data suggested that ubiquitination level was altered in cells transferred with the mutated plasmids.ConclusionCompound heterozygous pathogenic variants c.319 T > C and c.347 C > T in CFAP410 caused CORD with macular staphyloma. The pathogenic mechanisms may be associated with alternations of protein stability and degradation through the ubiquitin-proteasome pathway.

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Section: Resultsmentioning

confidence: 99%

Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma

Yang,

Li,

Yang

et al. 2023

Front. Med.

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“…Maats1 (Cilia and Flagella associated protein 91) has been identified as an important component of sperm flagellum structure and has not previously been described in the retina [85]. Mutations in the cilia and flagella-associated protein family have been linked with retinitis pigmentosa in familial amyotrophic lateral sclerosis [86].…”

Section: High-fat Diet May Affect Expression Of Genes Involved In Rpe Function and Ciliogenesis In Germ-free Micementioning

confidence: 99%

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

Dao

Xie

Nadeem

et al. 2021

Cells

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The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.

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“… 11 C21orf2 variant‐related retinopathies have two distinct phenotypes: one that solely affects the retina (OMIM #617547) and one with skeletal conditions such as axial spondylometaphyseal dysplasia (SMD) or Jeune Syndrome 12 (OMIM #602271) in addition to retinal manifestations. C21orf2 variants have also been implicated in the development of amyotrophic lateral sclerosis (ALS), 13 leading to a variety of RP phenotypes. In this report, we describe the ocular and systemic manifestations of previously reported C21orf2 variant‐associated retinopathies in the literature, as well as present two new cases of siblings with a novel homozygous c.26 T > C (p.Leu9Pro) variant.…”

Section: Introductionmentioning

confidence: 99%

C21orf2 variants causing inherited retinal disease: A review of what we know and a report of two new suspected cases

Shinbashi

Jewell

Randolph

et al. 2023

Clinical Case Reports

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Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation

Cited by 9 publications

References 5 publications

Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma

Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

C21orf2 variants causing inherited retinal disease: A review of what we know and a report of two new suspected cases

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