GATA1 – Cutaneous Porphyria

X-linked congenital erythropoietic porphyria (CEP) has been reported in three hemizygous male probands carrying the recurrent GATA1 variant c.646C>T (p.Arg216Trp) (PMID:25251786). These individuals presented with dyserythropoietic anemia (HP:0010972), thrombocytopenia (HP:0001873) and persistence of fetal hemoglobin. No multi-generational segregation data are available, and all cases are sporadic hemizygotes.

Functional characterization of cis-acting UROS promoter mutations in CEP revealed that a c.-70T>C transition in a GATA1 consensus binding element markedly reduces erythroid-specific transcription to 3% of wild-type activity and disrupts GATA1 binding in EMSA assays (PMID:11254675). This mechanistic evidence supports a pathogenic role for GATA1 variants in CEP via impaired regulation of UROS expression.

Key Take-home: The recurrent GATA1 c.646C>T (p.Arg216Trp) variant is an emerging cause of X-linked CEP, warranting inclusion of GATA1 in molecular diagnostic panels for porphyria.

References

• European journal of haematology • 2015 • Congenital erythropoietic porphyria linked to GATA1-R216W mutation: challenges for diagnosis. PMID:25251786
• The Journal of clinical investigation • 2001 • Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. PMID:11254675

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