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Leucine zipper transcription factor-like 1 (LZTFL1) encodes a ciliary protein implicated in Bardet-Biedl syndrome and related ciliopathies (ciliopathy). LZTFL1 localizes to the primary cilium and regulates protein trafficking via adaptor protein complexes 1 and 2, critical for photoreceptor and renal epithelial function.
Compound heterozygous LZTFL1 variants have been reported in 2 unrelated families (4 affected individuals) presenting with rod–cone dystrophy, cognitive impairment, renal dysfunction and mesoaxial polydactyly—an uncommon digit anomaly in ciliopathies (PMID:23692385). Affected twins harbored c.260T>C (p.Leu87Pro) and c.778G>T (p.Arg260Ter) in trans, with marked reduction of LZTFL1 transcript and protein in patient fibroblasts.
Additional case series confirm a spectrum of biallelic LZTFL1 mutations—including missense, nonsense, frameshift and splice site changes—across BBS-like ciliopathy phenotypes. Recurrent mesoaxial polydactyly in all reported families suggests a diagnostic hallmark prompting early LZTFL1 sequencing.
Functional studies in Lztfl1 knockout mice demonstrate low birth weight, adult-onset obesity, shortened photoreceptor outer segments, mislocalized rhodopsin and increased apoptosis in photoreceptors, recapitulating human retinal degeneration (PMID:27312011). In vitro, LZTFL1 directly binds AP-1 and AP-2 to regulate transferrin receptor 1 trafficking; loss of LZTFL1 reduces TfR1 internalization without affecting other receptor pathways (PMID:31895934).
No conflicting reports have been published to date. The concordance of biallelic LZTFL1 variants with classical BBS features, consistent segregation and robust in vivo and in vitro functional data support a disease mechanism of loss-of-function leading to ciliary trafficking defects.
Key Take-home: Biallelic LZTFL1 variants cause an autosomal recessive ciliopathy subtype characterized by mesoaxial polydactyly, retinal degeneration and cognitive impairment—genetic testing for LZTFL1 should be prioritized in such presentations.
Gene–Disease AssociationModerate2 unrelated families (4 probands), consistent segregation and supportive functional data Genetic EvidenceModerateCompound heterozygous missense and nonsense variants in 2 families with classical ciliopathy phenotypes Functional EvidenceModerateKnockout mouse recapitulates retinal degeneration and trafficking assays confirm loss-of-function |