LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome

Bozal-Basterra, Laura; Gonzalez-Santamarta, María; Muratore, Veronica; Bermejo-Arteagabeitia, Aitor; Fonseca, Carolina Da; Barroso-Gomila, Orhi; Azkargorta, Mikel; Iloro, Ibón; Pampliega, Olatz; Andrade, Ricardo; Martín-Martín, Natalia; Branon, Tess C; Ting, Alice Y.; Rodríguez, José Antonio; Carracedo, Arkaitz; Elortza, Félix; Sutherland, James D.; Barrio, Rosa

doi:10.7554/elife.55957

Cited by 29 publications

(44 citation statements)

References 89 publications

(134 reference statements)

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“…Another important actin binding protein implicated in ciliogenesis is leucine zipper protein 1 (LUZP1) ( Wang and Nakamura, 2019 ). In cycling cells, LUZP1 localizes to the pericentriolar matrix at the proximal end of each centriole, the actin cytoskeleton and the midbody ( Bozal-Basterra et al, 2020 ). In cell cycle-arrested cells, LUZP1 localizes to the basal body and to the ciliary axoneme.…”

Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

“…However, truncated mutant forms of SALL1 that cause TBS1 appear to interact with LUZP1 ( Bozal-Basterra et al, 2018 ). This interaction causes LUZP1 degradation through the ubiquitin proteasome system, since inhibition of the proteasome in TBS1 cells lead to accumulation of LUZP1 ( Bozal-Basterra et al, 2020 ). Loss of LUZP1 results in reduced actin polymerization, increased cilia incidence and length, and increased Shh signaling ( Bozal-Basterra et al, 2020 ; Gonçalves et al, 2020 ).…”

Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

“…This interaction causes LUZP1 degradation through the ubiquitin proteasome system, since inhibition of the proteasome in TBS1 cells lead to accumulation of LUZP1 ( Bozal-Basterra et al, 2020 ). Loss of LUZP1 results in reduced actin polymerization, increased cilia incidence and length, and increased Shh signaling ( Bozal-Basterra et al, 2020 ; Gonçalves et al, 2020 ). In contrast, over-expression of LUZP1 in TBS1 cells resulted in increased levels of F-actin and reduced ciliogenesis to normal levels, suggesting that LUZP1 is a potential therapeutic target for the treatment of TBS1 ( Bozal-Basterra et al, 2020 ).…”

Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

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Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Smith

Lake

Johnson

2020

Front. Cell Dev. Biol.

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Primary cilia are microtubule-based organelles that extend from the apical surface of most mammalian cells, forming when the basal body (derived from the mother centriole) docks at the apical cell membrane. They act as universal cellular “antennae” in vertebrates that receive and integrate mechanical and chemical signals from the extracellular environment, serving diverse roles in chemo-, mechano- and photo-sensation that control developmental signaling, cell polarity and cell proliferation. Mutations in ciliary genes cause a major group of inherited developmental disorders called ciliopathies. There are very few preventative treatments or new therapeutic interventions that modify disease progression or the long-term outlook of patients with these conditions. Recent work has identified at least four distinct but interrelated cellular processes that regulate cilia formation and maintenance, comprising the cell cycle, cellular proteostasis, signaling pathways and structural influences of the actin cytoskeleton. The actin cytoskeleton is composed of microfilaments that are formed from filamentous (F) polymers of globular G-actin subunits. Actin filaments are organized into bundles and networks, and are attached to the cell membrane, by diverse cross-linking proteins. During cell migration, actin filament bundles form either radially at the leading edge or as axial stress fibers. Early studies demonstrated that loss-of-function mutations in ciliopathy genes increased stress fiber formation and impaired ciliogenesis whereas pharmacological inhibition of actin polymerization promoted ciliogenesis. These studies suggest that polymerization of the actin cytoskeleton, F-actin branching and the formation of stress fibers all inhibit primary cilium formation, whereas depolymerization or depletion of actin enhance ciliogenesis. Here, we review the mechanistic basis for these effects on ciliogenesis, which comprise several cellular processes acting in concert at different timescales. Actin polymerization is both a physical barrier to both cilia-targeted vesicle transport and to the membrane remodeling required for ciliogenesis. In contrast, actin may cause cilia loss by localizing disassembly factors at the ciliary base, and F-actin branching may itself activate the YAP/TAZ pathway to promote cilia disassembly. The fundamental role of actin polymerization in the control of ciliogenesis may present potential new targets for disease-modifying therapeutic approaches in treating ciliopathies.

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Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

Section: Actin Binding Proteins Ciliogenesis and Cilia Maintenancementioning

confidence: 99%

See 1 more Smart Citation

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Smith

Lake

Johnson

2020

Front. Cell Dev. Biol.

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“…In addition, some authors proposed the involvement of SALL1 in the regulation of higher-order chromatin structures and hypothesized that the protein may be a component of a distinct heterochromatin-dependent silencing process [ 10 , 11 ]. Recently, studies have found that SALL1 can interact with ciliogenesis suppressors CCP110 and CEP97 and mutations in SALL1 may disrupt the formation and function of cilia [ 1 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

et al. 2021

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Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

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“…In addition, some authors proposed the involvement of SALL1 in the regulation of higher-order chromatin structures and hypothesized that the protein may be a component of a distinct heterochromatin-dependent silencing process [10,11]. Recently, studies have found that SALL1 can interact with ciliogenesis suppressors CCP110 and CEP97 and mutations in SALL1 may disrupt the formation and function of cilia [1,12].…”

Section: Introductionmentioning

confidence: 99%

Whole-exome Sequencing Identified a Novel Heterozygous Mutation of SALL1 and a New Homozygous Mutation of PTPRQ in a Chinese Family With Townes-brocks Syndrome and Hearing Loss

Yang

Yin

Zhiping

et al. 2021

Preprint

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Background: Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease (CHD). In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns.Methods: A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss.Results: Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation (ENST00000266688: c.1057_1057delC, p. L353SfsX8)) of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis.Conclusions: This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

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LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome

Cited by 29 publications

References 89 publications

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

Whole-exome Sequencing Identified a Novel Heterozygous Mutation of SALL1 and a New Homozygous Mutation of PTPRQ in a Chinese Family With Townes-brocks Syndrome and Hearing Loss

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