LZTFL1 – Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by retinal dystrophy, polydactyly, obesity, intellectual disability, and renal anomalies. Leucine zipper transcription factor-like 1 (LZTFL1), designated BBS17, has been implicated in BBS through biallelic pathogenic variants affecting ciliary protein trafficking.

In 2014, a pair of dizygotic twins presenting retinitis pigmentosa, bilateral mesoaxial polydactyly, cognitive impairment, and renal dysfunction were found to harbor compound heterozygous LZTFL1 variants c.260T>C (p.Leu87Pro) and c.778G>T (p.Arg108Ter), establishing LZTFL1 as a BBS gene and highlighting mesoaxial polydactyly as a distinctive feature prompting targeted sequencing (PMID:23692385).

A later report described a male proband with classical BBS signs plus severe short stature and pronounced intellectual disability carrying homozygous c.778G>T (p.Arg108Ter), expanding the phenotype and supporting a loss-of-function mechanism for LZTFL1 in BBS (PMID:38801250).

In a Turkish cohort of seven children with clinical BBS, one individual carried a homozygous LZTFL1 synonymous variant c.384G>A (p.Lys128=), suggesting further allelic heterogeneity though its pathogenicity remains uncertain (PMID:32686083).

Functional studies in Lztfl1 knockout mice revealed low birth weight followed by obesity, photoreceptor outer segment shortening, rhodopsin mislocalization, and increased photoreceptor apoptosis, recapitulating human rod-cone dystrophy and weight phenotypes and confirming the role of LZTFL1 in ciliary function (PMID:27312011).

In vitro assays demonstrated that LZTFL1 directly binds adaptor protein complexes AP-1 and AP-2 to mediate transferrin receptor 1 (TfR1) recycling; LZTFL1 loss impairs TfR1 internalization, indicating a mechanism by which disrupted ciliary trafficking leads to BBS features (PMID:31895934).

Together, biallelic LoF and missense variants in multiple families, segregation in trans, distinctive mesoaxial polydactyly, and concordant animal and cellular models provide strong clinical validity for LZTFL1 in BBS. Targeted LZTFL1 sequencing is recommended in patients with atypical polydactyly patterns.

Key Take-home: Autosomal recessive LZTFL1 mutations cause Bardet-Biedl syndrome with characteristic mesoaxial polydactyly and retinal dystrophy, supporting its inclusion in diagnostic gene panels.

References

• Clinical genetics • 2014 • Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations. PMID:23692385
• American journal of medical genetics. Part A • 2024 • LZTFL1, a rare cause of Bardet-Biedl syndrome: A new patient with severe short stature and moderate intellectual disability, more than casual associations? PMID:38801250
• Annals of human genetics • 2021 • Clinical and exome sequencing findings in seven children with Bardet-Biedl syndrome from Turkey. PMID:32686083
• Journal of genetics and genomics = Yi chuan xue bao • 2016 • Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice. PMID:27312011
• PLoS one • 2020 • Leucine zipper transcription factor-like 1 binds adaptor protein complex-1 and 2 and participates in trafficking of transferrin receptor 1. PMID:31895934

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