Cilia-related protein SPEF2 regulates osteoblast differentiation

Lehti, Mari S.; Henriksson, Henna; Rummukainen, Petri; Wang, Fan; Uusitalo‐Kylmälä, Liina; Kiviranta, Riku; Heino, Terhi J.; Kotaja, Noora; Sironen, Anu

doi:10.1038/s41598-018-19204-5

Cited by 27 publications

(22 citation statements)

References 40 publications

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“…67 A deficiency for cilia-related protein SPEF2 results in osteoblast differentiation defects. 68 In this study, we found that HH and WNT/β-catenin signaling is inverted in conditions of the primary cilia in Dhcr7 −/− and Insig1/2 cKO mice during intramembranous ossification. While both WNT/β-catenin and HH signaling pathways are essential for endochondral ossification as well as for the differentiation and maturation of cultured osteoblasts, 36 previous mouse genetic studies suggest that WNT/β-catenin signaling may be more dominant than HH signaling for osteogenesis in intramembranous ossification during skull formation.…”

Section: Discussionmentioning

confidence: 56%

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

et al. 2020

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Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7 (which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2 (which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation. Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.Bone Research (2020) 8:1; https://doi.

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Section: Discussionmentioning

confidence: 56%

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

et al. 2020

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“…This previous study proposed that the PCD-like phenotypes could be caused by a missense mutation in exon 3 of mouse Spef2 , while a stop-gain mutation at the C-terminus could be responsible for the spermatogenic defects 20. Similarly, ciliary abnormalities leading to bone growth defects and PCD-like symptoms were observed in the mice with a stop codon located after the Spef2 exon 2 23. Both of these PCD-associated Spef2 mutations in mice affected the N-terminus CH domain involved in regulating ciliary function (online supplementary figure 2).…”

Section: Discussionmentioning

confidence: 98%

Homozygous mutations inSPEF2induce multiple morphological abnormalities of the sperm flagella and male infertility

Liu

et al. 2019

J Med Genet

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BackgroundMale infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) is a genetically heterogeneous disorder. Previous studies revealed several MMAF-associated genes, which account for approximately 60% of human MMAF cases. The pathogenic mechanisms of MMAF remain to be illuminated.Methods and resultsWe conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF. Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified in two unrelated consanguineous families. Consistently, an Iranian subject from another cohort also carried a homozygous SPEF2 stop-gain variant (c.3240delT (p.Phe1080Leufs*2)). All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development. Notably, previous animal studies reported spontaneous mutations of SPEF2 causing sperm tail defects in bulls and pigs. Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected subjects.ConclusionsWe identified SPEF2 as a novel gene for human MMAF across the populations. Functional analyses suggested that the deficiency of SPEF2 in the mutated subjects could alter the localisation of other axonemal proteins.

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“…Mutations at different sites within SPEF2 produced disparate phenotypes. Depletion mutations at the N‐terminus caused hydrocephalus, growth retardation and an early death phenotype . A nonsense mutation in exon 28 caused PCD in mice.…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

et al. 2019

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Male patients with multiple morphological abnormalities of the sperm flagella (MMAF) are infertile and exhibit absent, short, coiled, bent and/or irregular sperm flagella. Mutations in the SPEF2 gene reduce sperm motility and cause sperm tail defects in animal models and humans. In the present study, we performed a genetic analysis on an MMAF patient and identified novel biallelic mutations in the SPEF2 gene. The biallelic mutations were confirmed by Sanger sequencing and in silico analysis revealed that, these variations were deleterious. The expression of truncated SPEF2 protein was reduced significantly in the patient's spermatozoa. The spermatozoa harbored biallelic mutations and showed severe ultrastructural defects in the axoneme and mitochondrial sheath. Our data suggest that biallelic mutations in SPEF2 can cause severe sperm flagellum defects, thus providing a novel candidate genetic pathogen for the human MMAF phenotype.

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Cilia-related protein SPEF2 regulates osteoblast differentiation

Cited by 27 publications

References 40 publications

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Homozygous mutations inSPEF2induce multiple morphological abnormalities of the sperm flagella and male infertility

Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

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