2. Academic Validation
  3. Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

  • Am J Hum Genet. 2017 Oct 5;101(4):552-563. doi: 10.1016/j.ajhg.2017.08.017.
Roberta De Mori 1,  Marta Romani 2,  Stefano D'Arrigo 3,  Maha S Zaki 4,  Elisa Lorefice 5,  Silvia Tardivo 5,  Tommaso Biagini 6,  Valentina Stanley 7,  Damir Musaev 7,  Joel Fluss 8,  Alessia Micalizzi 1,  Sara Nuovo 9,  Barbara Illi 10,  Luisa Chiapparini 11,  Lucia Di Marcotullio 12,  Mahmoud Y Issa 4,  Danila Anello 5,  Antonella Casella 5,  Monia Ginevrino 13,  Autumn Sa'na Leggins 7,  Susanne Roosing 14,  Romina Alfonsi 12,  Jessica Rosati 15,  Rachel Schot 16,  Grazia Maria Simonetta Mancini 16,  Enrico Bertini 17,  William B Dobyns 18,  Tommaso Mazza 6,  Joseph G Gleeson 7,  Enza Maria Valente 19
Affiliations

Affiliations

  • 1 Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Biological and Environmental Sciences, University of Messina, Messina 98125, Italy.
  • 2 Molecular Genetics Laboratory, GENOMA Group, Rome 00138, Italy.
  • 3 Developmental Neurology Division, Foundation IRCCS Neurological Institute Carlo Besta, Milan 20133, Italy.
  • 4 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 5 Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy.
  • 6 IRCCS Casa Sollievo della Sofferenza, Laboratory of Bioinformatics, San Giovanni Rotondo (FG) 71013, Italy.
  • 7 Laboratory for Pediatric Brain Diseases, Rady Children's Institute for Genomic Medicine, University of California, San Diego, Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
  • 8 Pediatric Neurology Unit, Geneva Children's Hospital, 1211 Genève 4, Switzerland.
  • 9 Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Medicine and Surgery, University of Salerno, Salerno 84081, Italy.
  • 10 Institute of Molecular Biology and Pathology, National Research Council, Rome 00185, Italy.
  • 11 Neuroradiology Department, Foundation IRCCS Neurological Institute Carlo Besta, Milan 20133, Italy.
  • 12 Department of Molecular Medicine and Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University, Rome 00161, Italy.
  • 13 Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy.
  • 14 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
  • 15 IRCCS Casa Sollievo della Sofferenza, Laboratory of Cellular Reprogramming, San Giovanni Rotondo (FG) 71013, Italy.
  • 16 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CN, the Netherlands.
  • 17 Laboratory of Molecular Medicine, Unit of Neuromuscular and NeuroDegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital IRCCS, Rome 00146, Italy.
  • 18 Departments of Pediatrics and Neurology, University of Washington, Seattle, WA 98101, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 19 Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome 00143, Italy; Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy. Electronic address: [email protected].
PMID: 28965847 DOI: 10.1016/j.ajhg.2017.08.017
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.

Keywords

GLI3; Joubert syndrome; SUFU; Sonic Hedgehog; ciliopathies; congenital ataxia; developmental defects; hypomorphic variants; molar tooth sign; polymicrogyria.

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