LZTR1 – Noonan Syndrome

LZTR1 encodes a BTB-Kelch adaptor for CUL3 ubiquitin ligase, regulating proteasomal degradation of RAS-family GTPases. Mutations in LZTR1 cause both autosomal dominant and autosomal recessive forms of Noonan syndrome, a multisystem RASopathy characterized by distinctive facial features, short stature, developmental delay, intellectual disability, and hypertrophic cardiomyopathy (PMID:32623905).

Clinical genetic data support a definitive association: 12 families with biallelic LZTR1 variants including loss-of-function and missense changes in 23 affected children confirm autosomal recessive inheritance, while multiple de novo heterozygous variants establish autosomal dominant transmission (PMID:29469822).

Segregation analyses reveal full co-segregation of biallelic variants in affected sibships and absence of disease in heterozygous carriers, with a total of 23 affected relatives observed across families (PMID:29469822).

The variant spectrum includes recurrent missense substitutions (e.g., c.850C>T (p.Arg284Cys)) and predicted loss-of-function alleles. c.850C>T (p.Arg284Cys) has been observed in dominantly inherited Noonan syndrome with tumor predisposition (PMID:30664951).

Functional assays in patient-derived iPSC cardiomyocytes recapitulate a hyperactive RAS-MAPK signature and cellular hypertrophy that is rescued by intronic CRISPR repair, confirming a loss-of-function mechanism. Lztr1-null zebrafish show hypertrophic cardiomyopathy and vascular malformations, reinforcing pathophysiological concordance with human disease (PMID:32623905; PMID:31883238).

Biochemical studies demonstrate that dominant NS-causing LZTR1 mutations impair Kelch-domain substrate recognition, leading to RAS accumulation and MAPK pathway upregulation (PMID:30481304).

Integration of robust genetic and experimental evidence establishes a definitive gene–disease association. LZTR1 variant testing is essential for molecular diagnosis, family counseling, and emerging personalized therapies, including CRISPR-based approaches.

Key Take-home: LZTR1 loss-of-function drives Noonan syndrome via RAS-MAPK dysregulation, and early genetic diagnosis enables targeted management and potential gene-editing therapies.

References

• Circulation • 2020 • Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy. PMID:32623905
  
• Genetics in Medicine • 2018 • Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. PMID:29469822
  
• Molecular Genetics & Genomic Medicine • 2020 • Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish. PMID:31883238
  
• Human Molecular Genetics • 2019 • Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. PMID:30481304
  
• European Journal of Medical Genetics • 2020 • Oligo-astrocytoma in LZTR1-related Noonan syndrome. PMID:30664951

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