FAM20A – Enamel-Renal Syndrome (Amelogenesis Imperfecta Type IG)

FAM20A deficiency causes an autosomal recessive enamel-renal syndrome (amelogenesis imperfecta type IG, ERS) characterized by severe hypoplastic enamel, gingival hyperplasia, and nephrocalcinosis presenting in early childhood. Affected individuals exhibit failed or delayed tooth eruption, intra-pulpal calcifications, and variable renal calcifications requiring long-term monitoring.

Genetic evidence comprises at least 69 probands across over 50 unrelated families, with consanguineous pedigrees and homozygous or compound heterozygous loss-of-function variants disrupting FAM20A ([PMID:33994680]). Case reports document recurrent frameshift and nonsense variants leading to protein truncation and nonsense-mediated decay.

Segregation analysis reveals 30 additional affected relatives in multiplex families, confirming autosomal recessive inheritance and variant pathogenicity ([PMID:33994680]). The variant spectrum is dominated by frameshift alleles such as c.734_735delAG (p.Glu245GlyfsTer11) ([PMID:31131889]) and a Brazilian founder c.1447del (p.Glu483LysfsTer24) ([PMID:30394349]), with a smaller number of missense changes affecting the kinase-like domain.

Functional studies demonstrate that FAM20A is a secretory pathway pseudokinase essential for activation and extracellular secretion of FAM20C. Fam20a null mice exhibit ectopic renal calcifications and enamel defects analogous to human ERS ([PMID:23468644]), and co-expression assays show loss of extracellular FAM20C in Fam20a-deficient cells ([PMID:27292199]).

Structural analyses reveal FAM20A binds ATP in an inverted orientation and forms dimers critical for allosteric activation of FAM20C, elucidating a loss-of-function mechanism through impaired kinase complex formation ([PMID:28432788]).

Cumulatively, the robust genetic and experimental evidence supports a Definitive FAM20A–ERS gene-disease association. Biallelic FAM20A loss-of-function variants should be included in genetic diagnostic panels for amelogenesis imperfecta to guide multidisciplinary management and renal surveillance. Key Take-home: early molecular diagnosis of FAM20A-related ERS enables targeted dental rehabilitation and prevention of renal complications.

References

• PLoS genetics • 2013 • FAM20A mutations can cause enamel-renal syndrome (ERS). PMID:23468644
• Indian journal of nephrology • 2021 • Enamel Renal Syndrome: A Systematic Review. PMID:33994680
• Journal of periodontal research • 2019 • Transcriptome analysis of gingival tissues of enamel-renal syndrome. PMID:31131889
• European journal of medical genetics • 2019 • Enamel renal syndrome: A novel homozygous FAM20A founder mutation in 5 new Brazilian families. PMID:30394349
• PLoS genetics • 2016 • FAM20A binds to and regulates FAM20C localization. PMID:27292199
• eLife • 2017 • Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding. PMID:28432788

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