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.

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects / De Mori, Roberta; Romani, Marta; D'Arrigo, Stefano; Zaki, Maha S; Lorefice, Elisa; Tardivo, Silvia; Biagini, Tommaso; Stanley, Valentina; Musaev, Damir; Fluss, Joel; Micalizzi, Alessia; Nuovo, Sara; Illi, Barbara; Chiapparini, Luisa; Di Marcotullio, Lucia; Issa, Mahmoud Y; Anello, Danila; Casella, Antonella; Ginevrino, Monia; Leggins, Autumn Sa'na; Roosing, Susanne; Alfonsi, Romina; Rosati, Jessica; Schot, Rachel; Mancini, Grazia Maria Simonetta; Bertini, Enrico; Dobyns, William B; Mazza, Tommaso; Gleeson, Joseph G; Valente, ENZA MARIA. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - ELETTRONICO. - 101:4(2017), pp. 552-563. [10.1016/j.ajhg.2017.08.017]

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

LOREFICE, ELISA;Tardivo, Silvia;Biagini, Tommaso;Nuovo, Sara;CHIAPPARINI, LUISA;Di Marcotullio, Lucia;Alfonsi, Romina;Rosati, Jessica;Bertini, Enrico;VALENTE, ENZA MARIA
2017

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.
2017
GLI3; Joubert syndrome; SUFU; Sonic Hedgehog; ciliopathies; congenital ataxia; developmental defects; hypomorphic variants; molar tooth sign; polymicrogyria; Abnormalities, Multiple; Bone Diseases, Developmental; Cells, Cultured; Cerebellum; Child; Cohort Studies; Craniofacial Abnormalities; Eye Abnormalities; Female; Fibroblasts; Gene Expression Regulation, Developmental; Hedgehog Proteins; Humans; Kidney Diseases, Cystic; Kruppel-Like Transcription Factors; Male; Nerve Tissue Proteins; Repressor Proteins; Retina; Sequence Analysis, DNA; Signal Transduction; Skin; Zinc Finger Protein Gli3; Genes, Recessive; Mutation, Missense
01 Pubblicazione su rivista::01a Articolo in rivista
Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects / De Mori, Roberta; Romani, Marta; D'Arrigo, Stefano; Zaki, Maha S; Lorefice, Elisa; Tardivo, Silvia; Biagini, Tommaso; Stanley, Valentina; Musaev, Damir; Fluss, Joel; Micalizzi, Alessia; Nuovo, Sara; Illi, Barbara; Chiapparini, Luisa; Di Marcotullio, Lucia; Issa, Mahmoud Y; Anello, Danila; Casella, Antonella; Ginevrino, Monia; Leggins, Autumn Sa'na; Roosing, Susanne; Alfonsi, Romina; Rosati, Jessica; Schot, Rachel; Mancini, Grazia Maria Simonetta; Bertini, Enrico; Dobyns, William B; Mazza, Tommaso; Gleeson, Joseph G; Valente, ENZA MARIA. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - ELETTRONICO. - 101:4(2017), pp. 552-563. [10.1016/j.ajhg.2017.08.017]
File allegati a questo prodotto
File Dimensione Formato  
DeMori_Hypomorphic-Recessive-Variants_2017.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.13 MB
Formato Adobe PDF
2.13 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1085265
Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 41
  • ???jsp.display-item.citation.isi??? 39
social impact