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Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet–Biedl syndrome with situs inversus and insertional polydactyly
  1. Vincent Marion1,
  2. Fanny Stutzmann1,
  3. Marion Gérard2,
  4. Charlie De Melo1,
  5. Elise Schaefer1,3,
  6. Aurélie Claussmann1,
  7. Sophie Hellé1,
  8. Valérie Delague4,
  9. Eric Souied5,
  10. Catherine Barrey6,
  11. Alain Verloes2,
  12. Corinne Stoetzel1,
  13. Hélène Dollfus1,3,7
  1. 1Laboratoire Physiopathologie des syndromes rares héréditaires, INSERM-AVENIR, Université de Strasbourg, Strasbourg, France
  2. 2Unité de Génétique Clinique, Hôpital Robert Debré, Paris, France
  3. 3Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  4. 4Laboratoire de Génétique Médicale et Genomique fonctionelle, UFR de Médecine, Marseille, France
  5. 5Hospitalier Intercommunal de Creteil, avenue de Verdun, 1 Creteil, France
  6. 6CHU de Caen, Caen, France
  7. 7Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  1. Correspondence to Dr Vincent Marion, Laboratoire de Génétique Médicale EA 3949 Inserm Avenir, Université de Strasbourg, 11 rue Humann, Strasbourg 67085, France; vincent.marion{at}


Background Bardet–Biedl Syndrome (BBS) is an emblematic recessive genetically highly heterogeneous ciliopathy characterised mainly by polydactyly, retinitis pigmentosa, obesity, cognitive impairment, and kidney dysfunction. The 16 BBS genes known to date are implied in the primary cilia related cellular pathways.

Methods and results Single nucleotide polymorphism (SNP) array analysis followed by exome sequencing was performed in a consanguineous family diagnosed with BBS with unusual developmental features, namely situs inversus and insertional polydactyly. A homozygous 5 bp deletion (NM_020347.2:c.402-406del, p.Pro136ThrfsX5) in LZTFL1 was identified. No LZTFL1 transcript was found in the patient's fibroblasts and no protein could be detected. The sonic hedgehog (Shh) pathway analysis conducted on the patient's fibroblast showed a significant increase in Smo. Patched1 as well as the downstream target GLI2 were also found to be upregulated, indicating an overall massive activation of the Shh signalling in the absence of LZTFL1.

Conclusion LZTFL1, encoding the human leucine zipper transcription factor like 1, has been recently shown to be an important negative regulator of BBSome ciliary trafficking and Shh signalling. This study shows that absence of LZTFL1 leads to a BBS phenotype with enhanced developmental abnormalities associated with cellular Shh dysfunction. LZTFL1 is a novel BBS gene (BBS17).

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  • Funding This work was partly funded by UNADEV, RETINA France, FORMICOEUR and BARDET-BIEDL France associations and by the AVENIR INSERM program since 2007.

  • Competing interests None.

  • Ethics approval The ethics approval was provided by Hôpital Robert Debré -Paris and Hôpitaux Universitaires de Strasbourg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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