POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome.
The POLG genes were sequenced in two unrelated patients presenting with Alpers syndrome. The novel c.3626_3629dupGATA and the c.3643+2T>C alleles were associated in trans with p.A467T and p.[W748S;E1143G], respectively. POLG transcripts from skin fibroblasts showed complete exon 22 skipping for patient 2, but surprisingly partial exon 22 skipping from the c.3626_3629dupGATA for patient 1. The creation of a putative exonic splicing silencer could be responsible for the splicing anomaly observed in patient 1. Both c.3643+2T>C and c.3626_3629dupGATA create a premature termination codon and a low polymerase γ activity in skin fibroblasts is responsible for the severe phenotype in these patients.
Mousson de Camaret
Bénédicte
B
Centre de Biologie et de Pathologie Est - CHU Lyon, Service des Maladies Héréditaires du Métabolisme, 69677 Bron, France. benedicte.mousson-de-camaret@chu-lyon.fr
Chassagne
Maïté
M
Mayençon
Martine
M
Padet
Sylvie
S
Crehalet
Hervé
H
Clerc-Renaud
Pascale
P
Rouvet
Isabelle
I
Zabot
Marie-Thérèse
MT
Rivier
François
F
Sarda
Pierre
P
des Portes
Vincent
V
Bozon
Dominique
D
D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000175:diagnosis / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D012326:RNA Splicing; D017422:Sequence Analysis, DNA
D018389:Codon, Nonsense; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human