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

Roberta De Mori, Marta Romani, Stefano D'Arrigo, Maha S. Zaki, Elisa Lorefice, Silvia Tardivo, Tommaso Biagini, Valentina Stanley, Damir Musaev, Joel Fluss, Alessia Micalizzi, Sara Nuovo, Barbara Illi, Luisa Chiapparini, Lucia Di Marcotullio, Mahmoud Y. Issa, Danila Anello, Antonella Casella, Monia Ginevrino, Autumn Sa na LegginsSusanne Roosing, Romina Alfonsi, Jessica Rosati, Rachel Schot, Grazia Maria Simonetta Mancini, Enrico Bertini, William B. Dobyns, Tommaso Mazza, Joseph G. Gleeson, Enza Maria Valente

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)552-563
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - Oct 5 2017
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to the families for their cooperation to the study. This work was supported by European Research Council ( ERC StG 260888 ), Telethon Foundation Italy (grant GGP13146 ), Italian Ministry of Health ( Ricerca Finalizzata grant NET-2013-02356160 ), and Pierfranco and Luisa Mariani Foundation ( PADAPORT project) to E.M.V.; R01NS048453 , P01HD070494 , SFARI award 275275 , and the Howard Hughes Medical Institute to J.G.G.; the ErasmusMC MRace project ( 104673 ) to G.M.S.M.; and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (award R01NS050375 ) to W.B.D.

Publisher Copyright:
© 2017 American Society of Human Genetics


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


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