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

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).

[1]  V. Sheffield,et al.  A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened , 2011, PLoS genetics.

[2]  H. Dollfus,et al.  Retinal dystrophy in Bardet–Biedl syndrome and related syndromic ciliopathies , 2011, Progress in Retinal and Eye Research.

[3]  K. L. Tucker,et al.  Primary cilia and organogenesis: is Hedgehog the only sculptor? , 2011, Cell and Tissue Research.

[4]  Lance Lee.  Mechanisms of mammalian ciliary motility: Insights from primary ciliary dyskinesia genetics. , 2011, Gene.

[5]  J. Mandel,et al.  Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes. , 2011, European journal of medical genetics.

[6]  M. Ascenzi,et al.  Ofd1 is required in limb bud patterning and endochondral bone development. , 2011, Developmental biology.

[7]  K. Dahan,et al.  A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  S. Levy,et al.  Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy , 2010, Nature Genetics.

[9]  S. Gygi,et al.  The Conserved Bardet-Biedl Syndrome Proteins Assemble a Coat that Traffics Membrane Proteins to Cilia , 2010, Cell.

[10]  V. Sheffield,et al.  BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly , 2010, Proceedings of the National Academy of Sciences.

[11]  Nicholas Katsanis,et al.  Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. , 2009, The Journal of clinical investigation.

[12]  A. Moorman,et al.  Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data , 2009, Nucleic acids research.

[13]  V. Sheffield,et al.  A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. , 2008, Developmental cell.

[14]  James Briscoe,et al.  Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network , 2008, Development.

[15]  V. Sheffield,et al.  A Core Complex of BBS Proteins Cooperates with the GTPase Rab8 to Promote Ciliary Membrane Biogenesis , 2007, Cell.

[16]  E. Souied,et al.  Recurrent insertional polydactyly and situs inversus in a Bardet‐Biedl syndrome family , 2007, American journal of medical genetics. Part A.

[17]  Tanya M. Teslovich,et al.  Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome , 2003, Nature.

[18]  U. C. Patel,et al.  The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. , 1999, American journal of human genetics.

[19]  L. Shaffer,et al.  Monosomy 1p36 , 1999, Journal of medical genetics.

[20]  P. Beales,et al.  New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey , 1999, Journal of medical genetics.

[21]  A. Moerman,et al.  Bardet-Biedl syndrome with preaxial polydactyly. , 1999, American journal of medical genetics.

[22]  L. Biesecker,et al.  GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome , 1997, Nature Genetics.

[23]  L. Biesecker,et al.  Report from the workshop on Pallister-Hall syndrome and related phenotypes. , 1996, American journal of medical genetics.