Fuctional chractererization of five protoporphyrinogen oxidase missense mutations found in Argentinean Variegate patients

M MENDEZ, ; GRANATA BX; MORAN JIMENEZ MJ; PARERA VE; ENRIQUEZ DE SALAMANCA R; ROSSETTI MV,

JOURNAL OF INHERITED METABOLIC DISEASE

SPRINGER

Año: 2011 p. 1 - 7

0141-8955

A partial deficiency in protoporphyrinogen oxidase (PPOX) produces the acute/cutaneous (or mixed) variegate porphyria (VP), the third  most frequent in porphyria in Argentina. This autosomal dominant disorder is clinically characterized by skin lesions and/or acute neurovisceral attacks. The precise diagnosis of patients with an symptomatic VP is essential to provide accurate treatment. It is also critical to identify asymptomatic relatives to avoid precipitating factors and prevent acute attacks. Functional consequences of five PPOX missense mutations were evaluated in a prokaryotic expression system. Three mutations were found in families previously reported c.101A>T (p.E34V), c.670T>G (W224G), c.995G>C (G332A) and two were novel findings c.227C>T (p.S76F), c.1265A>G (p.Y422C). All mutations were identified in heterozygotes with reduced PPOX activity and variable clinical expression of the disease, including asymptomatic cases. Prokaryotic expression showed that all five missense mutations decreased the PPOX activity, demonstrating their detrimental effect on enzyme función, and thus, providing evidence for their causative role in VP. These results reinforce the importance of molecular genetic analysis for VP diagnosis and especially the usefulness of prokaryotic expression of missense mutations to assess their deleterious effect on PPOX activity Runnig Title:  Expression of PPOX missense mutations