MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

The ß-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in ß-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in ß-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet ß-cell activity.

Picnodisostose: relato de dois casos / Pycnodysostosis: report of two cases

Picnodisostose (PYCD) é uma rara displasia esquelética autossômica recessiva, decorrente de defeito no gene codificador da enzima catepsina K, caracterizada por baixa estatura (BE), osteoesclerose, acroosteólise, deformidades crânio-faciais e fragilidade óssea. Embora a BE seja característica, deficiência de GH tem sido relatada apenas em parte dos casos de PYCD. Apresentamos dois casos isolados, com quadros clínico-radiológicos característicos. Caso 1: 9 anos, masculino, pais consangüíneos, apresentando BE, osteoesclerose, fragilidade óssea, exoftalmia bilateral, fronte ampla, braquicefalia, alargamento das suturas cranianas, fontanelas abertas, micrognatia, implantação anormal dos dentes, braquidactilia, unhas distróficas e acrosteólise das falanges distais. Caso 2: 17 anos, masculino, com BE, nariz proeminente, braquicefalia, plastibasia, falha de fechamento de suturas e fontanelas, hipoplasia mandibular, dentição anormal, osteoesclerose difusa, braquidactilia, acrosteólise das falanges distais e aumento das pregas cutâneas nas mãos. Ambos apresentaram níveis basais normais de TSH, T4 livre, gonadotrofinas e testosterona, e da resposta do GH e do cortisol, durante teste farmacológico. Em conclusão, a PYCD parece ser uma condição heterogénea com apresentação clínica variável. Assim, embora não tenha sido observado nestes casos, mas tendo em vista as descrições prévias, consideramos importante que pacientes com PYCD sejam rotineiramente submetidos à avaliação hormonal.