title: 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.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Laboratoire Physiopathologiedes syndromes rareshéréditaires, INSERM-AVENIR, Université de Strasbourg, Strasbourg, France. vincent.marion@unistra.fr
authors.forename: Vincent
authors.initials: V
authors.lastname: Marion
authors.forename: Fanny
authors.initials: F
authors.lastname: Stutzmann
authors.forename: Marion
authors.initials: M
authors.lastname: Gérard
authors.forename: Charlie
authors.initials: C
authors.lastname: De Melo
authors.forename: Elise
authors.initials: E
authors.lastname: Schaefer
authors.forename: Aurélie
authors.initials: A
authors.lastname: Claussmann
authors.forename: Sophie
authors.initials: S
authors.lastname: Hellé
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
authors.forename: Eric
authors.initials: E
authors.lastname: Souied
authors.forename: Catherine
authors.initials: C
authors.lastname: Barrey
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
mesh_terms: D000328:Adult; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017689:Polydactyly / Q000235:genetics*; D012857:Situs Inversus / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C431701:LZTFL1 protein, human; D014157:Transcription Factors