L237P Substitution in the UROS Gene Causes X-linked Recessive Congenital Erythropoietic Porphyria in Pakistani Consanguineous Family Through Altered Uroporphyrinogen III Binding
L237P Substitution in the UROS Gene Causes X-linked Recessive Congenital Erythropoietic Porphyria in Pakistani Consanguineous Family Through Altered Uroporphyrinogen III Binding
Roshana Mukhtar1, Shaheen Shahzad1*, Sajid Rashid2, Maryam Rozi2, Madiha Rasheed3, Imran Afzal4 and Pakeeza Arzoo Shaiq5
ABSTRACT
Congenital erythropoietic porphyria (CEP) is an inherited heterogeneous metabolic disorder caused by an abnormal activity of uroporphyrinogen-III synthase (UROS), aminolevulinic acid and GATA1 (GATA binding factor 1) genes. The fundamental genetic cause of CEP has been linked to a sequence variant of UROS on chromosome 10q252-q263. The enzyme catalyzes the fourth step of heme synthesis pathway. The present study focused on the clinical assessment of CEP affected individuals in a Pakistani consanguineous family by Sanger sequencing of UROS gene to identify potential pathogenic sequence variants. CEP patients were identified using successive clinical tests. Blood samples of patients were collected and processed for genomic DNA extraction followed by Sanger sequencing to identify pathogenic mutations in UROS gene. Sequence analysis revealed a pathogenic missense mutation (c.935T>C [p. L237P]) in the exon 10.The sequence was further analysed in-silico to determine the effect of pathogenic mutation on protein structure. In-silico analysis and comparison between UROSL237P and UROSWT 3-dimensional structures revealed remarkable changes in the binding site of Urogen (3-[7, 12, 18-tris (2-carboxyethyl)-3, 8, 13, 17-tetrakis (carboxymethyl) 5, 10, 15, 20, 21, 22, 23, 24-octahydroporphyrin-2-yl] propanoic acid) due to narrowing of domain-I and domain-II (18.46-12.17Å) of UROSL237P as compared to UROSWT. This suggests that UROS L237P mutation may influence heme biosynthesis mechanism through altered Urogen binding mechanism. Therefore, we propose that the newly identified pathogenic missense variant (c.935T>C [p.L237P]) p.Gly439Ser) of the UROS gene causes CEP in a large consanguineous Pakistani family, possibly by hindering heme biosynthesis mechanism through altered Urogen binding mechanism.
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