Whole exome sequencing reveals novel <i>CEP104</i> mutations in a Chinese patient with Joubert syndrome

Luo, Minna; Cao, Li; Cao, Zhen; Ma, Shuyue; Shen, Yue; Yang, Di; Lü, Chao; Lin, Zaisheng; Liu, Zhimin; Yu, Yufei; Cai, Ruikun; Chen, Cuixia; Gao, Huafang; Wang, Xueyan; Cao, Muqing; Ma, Xu

doi:10.1002/mgg3.1004

Cited by 9 publications

(9 citation statements)

References 25 publications

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“…CEP104 was previously shown to be a causative gene for JBTS (27,28), and mutations of other JBTS-associated genes, such as ARL13B, cause defects in Hh signaling (47). We have provided evidence here that CEP104 is critical for the control of cilium-dependent Hh signaling.…”

Section: Discussionmentioning

confidence: 65%

“…Mutations in CEP104 are linked to JBTS (27,28). Intriguingly, mutations in JBTS-related genes are typically associated with abnormalities of Hh signaling caused by enhanced or reduced ciliary trafficking of Hh signal-related transmembrane proteins, such as Smo and GPR161 (19)(20)(21)(24)(25)(26).…”

Section: Cep104 Is Required For Hh Signal-induced Ciliary Trafficking Of Smo and Gpr161 And Gli1 Expressionmentioning

confidence: 99%

“…Centrosomal protein 104 (CEP104), an evolutionarily conserved protein, is encoded by CEP104, which was recently reported to be a causative gene for JBTS (27,28). CEP104 binds to CP110 and CEP97 and colocalizes with these proteins at the distal ends of both mother and daughter centrioles in nonciliated cells (29,30).…”

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confidence: 99%

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Roles of TOG and jelly-roll domains of centrosomal protein CEP104 in its functions in cilium elongation and Hedgehog signaling

Yamazoe

Nagai

Umeda

et al. 2020

Journal of Biological Chemistry

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Primary cilia are generated through the extension of the microtubule-based axoneme. Centrosomal protein 104 (CEP104) localizes to the tip of the elongating axoneme, and CEP104 mutations are linked to a ciliopathy, Joubert syndrome. Thus, CEP104 has been implicated in ciliogenesis. However, the mechanism by which CEP104 regulates ciliogenesis remains elusive. We report here that CEP104 is critical for cilium elongation but not for initiating ciliogenesis. We also demonstrated that the tumor-overexpressed gene (TOG) domain of CEP104 exhibits microtubule-polymerizing activity and that this activity is essential for the cilium-elongating activity of CEP104. Knockdown/rescue experiments showed that the N-terminal jelly-roll (JR) fold partially contributes to cilium-elongating activity of CEP104, but neither the zinc-finger region nor the SXIP motif is required for this activity. CEP104 binds to a centriole-capping protein, CP110, through the zinc-finger region and to a microtubule plus-end-binding protein, EB1, through the SXIP motif, indicating that the binding of CP110 and EB1 is dispensable for the cilium-elongating activity of CEP104. Moreover, CEP104 depletion does not affect CP110 removal from the mother centriole, which suggests that CEP104 functions after the removal of CP110. Lastly, we also showed that CEP104 is required for the ciliary entry of Smoothened and export of GPR161 upon Hedgehog signal activation and that the TOG domain plays a critical role in this activity. Our results define the roles of the individual domains of CEP104 in its functions in cilium elongation and Hedgehog signaling and should enhance our understanding of the mechanism underlying CEP104 mutation-associated ciliopathies.

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Section: Discussionmentioning

confidence: 65%

Section: Cep104 Is Required For Hh Signal-induced Ciliary Trafficking Of Smo and Gpr161 And Gli1 Expressionmentioning

confidence: 99%

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Roles of TOG and jelly-roll domains of centrosomal protein CEP104 in its functions in cilium elongation and Hedgehog signaling

Yamazoe

Nagai

Umeda

et al. 2020

Journal of Biological Chemistry

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“…Our patients with CEP104 variants, family 8800138; NM_014704:c.2356_2357insTT p.(Cys786Phefs*11) and family 9100012; NM_014704:c.1901_1902insT p.(Leu634Phefs*33) showed non-syndromic ID with no brain malformations such as cerebellar hypoplasia or pathognomonic molar tooth sign (MTS) (Figure 1C), previously reported for patients with JBTS carrying CEP104 mutations. 19,39 This may indicate that at least in some cases, CEP104 is less likely to cause brain malformations; rather, it can possibly affect higher cognitive and intellectual capabilities. Our patients with CEP290 variants manifested an extensive phenotypic spectrum compatible with known phenotypes related to CEP290 variants.…”

Section: Genetic Analysis Resultsmentioning

confidence: 99%

CEP104 and CEP290; Genes with Ciliary Functions Cause Intellectual Disability in Multiple Families

et al. 2021

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Background: Neurodevelopmental and intellectual impairments are extremely heterogeneous disorders caused by a diverse variety of genes involved in different molecular pathways and networks. Genetic alterations in cilia, highly-conserved organelles with sensorineural and signal transduction roles can compromise their proper functions and lead to so-called "ciliopathies" featuring intellectual disability (ID) or neurodevelopmental disorders as frequent clinical manifestations. Here, we report several Iranian families affected by ID and other ciliopathy-associated features carrying known and novel variants in two ciliary genes; CEP104 and CEP290. Methods: Whole exome and targeted exome sequencing were carried out on affected individuals. Lymphoblastoid cell lines (LCLs) derived from the members of affected families were established for two families carrying CEP104 mutations. RNA and protein expression studies were carried out on these cells using qPCR and Western blot, respectively. Results: A novel homozygous variant; NM_025114.3:c.7341_7344dupACTT p.(Ser2449Thrfs*8) and four previously reported homozygous variants; NM_025114.3:c.322C > T p.(Arg108*), NM_025114.3:c.4393C > T p.(Arg1465*), NM_025114.3:c.5668G > T p.(Gly1890*) and NM_025114.3:c.1666dupA p.(Ile556Asnfs*20) were identified in CEP290. In two other families, two novel homozygous variants; NM_014704:c.2356_2357insTT p.(Cys786Phefs*11) and NM_014704:c.1901_1902insT p.(Leu634Phefs*33) were identified in CEP104, another ciliary gene. qPCR and Western blot analyses showed significantly lower levels of CEP104 transcripts and protein in patients compared to heterozygous or normal family members. Conclusion:We emphasize the clinical variability and pleiotropic phenotypes due to the variants of these genes. In conclusion, our findings support the pivotal role of these genes in cognitive and neurodevelopmental features.

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“…PCR duplicates were removed by Picard tools. Variants and small InDels were called by Genome Analysis Toolkit (GATK), annotated with Ensembl Variant Effect Predictor (McLaren et al, 2016) and filtered as described previously (Luo et al, 2019). Finally, all the variants were annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al, 2015), and the variants from known causative genes of JBTS were analyzed with priority.…”

Section: Whole Exome Sequencing and Variants Analysismentioning

confidence: 99%

Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

Luo

Lin

et al. 2020

Front. Genet.

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Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.

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Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome

Cited by 9 publications

References 25 publications

Roles of TOG and jelly-roll domains of centrosomal protein CEP104 in its functions in cilium elongation and Hedgehog signaling

Roles of TOG and jelly-roll domains of centrosomal protein CEP104 in its functions in cilium elongation and Hedgehog signaling

CEP104 and CEP290; Genes with Ciliary Functions Cause Intellectual Disability in Multiple Families

Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

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