ArticleAmerican journal of human genetics2017
Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- European Association of Neuro-Oncology guideline on molecular testing of meningiomas for targeted therapy selection.Neuro-oncology · 2025Guideline
- COBT: a gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts.Genome medicine · 2026Article
- Ciliary-Mediated Mechanotransduction in Skeletal Development and Diseases.Results and problems in cell differentiation · 2026Review
- NIMA-related kinase family at the nexus of skeletal development and congenital arthrogryposis: coordinated regulation of cell cycle and ciliary dynamics.Frontiers in genetics · 2026Review
- Regulatory mechanisms governing GLI proteins in hedgehog signaling.Anatomical science international · 2025Review
- Genome-Based Advances in Modeling Renal Ciliopathies and Enhancing Patient Care.Kidney & blood pressure research · 2025Review
- Sculptors of cerebellar fissures and their potential as therapeutic targets for cerebellar dysfunction.Frontiers in cellular neuroscience · 2025Review
- Skeletal ciliopathy: pathogenesis and related signaling pathways.Molecular and cellular biochemistry · 2024Review
- MYCN in human development and diseases.Frontiers in oncology · 2024Review
- Pax3 lineage-specific deletion of Gpr161 is associated with spinal neural tube and craniofacial malformations during embryonic development.Disease models & mechanisms · 2023Article
- RecessiveJournal of personalized medicine · 2023Article
- Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.American journal of human genetics · 2023Article
- ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1.Life science alliance · 2022Article
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- The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies.Annual review of genomics and human genetics · 2022Review
- Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology.International journal of molecular sciences · 2022Review
- Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Clinical and genetic spectrums of 413 North African families with inherited retinal dystrophies and optic neuropathies.Orphanet journal of rare diseases · 2022Review
- Genotype-phenotype correlates in Joubert syndrome: A review.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
Corrections and comments
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Authors and funding
30 authors at 15 institutions in 5 countries.
Funding
Abstract
The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.
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Registered trials
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