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Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy  Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina.

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Presentation on theme: "Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy  Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina."— Presentation transcript:

1 Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy 
Orly Agamy, Bruria Ben Zeev, Dorit Lev, Barak Marcus, Dina Fine, Dan Su, Ginat Narkis, Rivka Ofir, Chen Hoffmann, Esther Leshinsky- Silver, Hagit Flusser, Sara Sivan, Dieter Söll, Tally Lerman-Sagie, Ohad S. Birk  The American Journal of Human Genetics  Volume 87, Issue 4, Pages (October 2010) DOI: /j.ajhg Copyright © 2010 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Sequential MRI Studies in PCCA
Images are of individual 4 of family A (Figure 2). (A) Age 8 months: a T1 coronal image at the level of the occipital lobes demonstrates a normal-looking brain. (B) Age 18 months: a T1 sagital image showing vermian atrophy with mild cerebral atrophy. (C) Age 3 years: a coronal image at the level of the occipital lobes demonstrates severe cerebellar and cerebral atrophy. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Genetic Mapping of the Disease-Associated Locus
Haplotypes of all four families on chromosome 4p15.2 are shown. The disease-associated haplotype is boxed. Additional microsatellite markers were used for fine mapping the candidate region identified by the genome-wide scan with the 10K SNP arrays. Families A and B are of Iraqi origin. Families C and D are of Iraqi and Moroccan origin. The minimum disease-associated haplotype lies between markers D4S425 and D4S391 for the “Iraqi” haplotype and between markers D4S1551 and rs for the “Moroccan” haplotype. Gray shading indicates the SepSecS position within the haplotype. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

4 Figure 3 SepSecS Mutations in PCCA Families
(A–C) The c.1001A>G SepSecS mutation in exon 8. Sequence analysis is shown for an affected individual (A), a carrier (B), and an unaffected individual (C) in families A and B. (D and E) The c.715G>A mutation in exon 6. Sequence analysis is shown for a carrier (D) and unaffected individuals (E) in families C and D. Affected individuals in families C and D were compound heterozygous for the two mutations. The arrows indicate the positions of the mutations. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Alignment of the Mutated Sequence Regions in Some Eukaryotic and Archaeal SepSecS Proteins The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Functional Studies of the SepSecS Mutations
In vivo assays of human SepSecS mutants. Formation of Sec-tRNASec in vivo is assayed by the ability of the wild-type human SepSecS and the mutant variants p.Lys284Thr, p,Ala239Thr, and p.Tyr334Cys to restore the benzyl-viologen-reducing activity of the selenoprotein FDHH in the E. coli ΔselA deletion strain. The Methanocaldococcus jannaschii PSTK is cotransformed to generate the Sep-tRNASec intermediate. K284T is a previously described inactive SepSecS mutant. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

7 Figure 6 Structure of Selenocysteine and Its Route of Biosynthesis
Seryl-tRNA synthetase attaches serine to tRNASec. (Top) Bacteria use selenocysteine synthase (SelA) to convert Ser-tRNASec directly to Sec-tRNASec. (Bottom) Eukaryotes and archaea employ a two-step conversion; a kinase (PSTK) provides the phosphorylated intermediate Sep-tRNASec, the required substrate of SepSecS (see text). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

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