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Mutations in PCYT1A, Encoding a Key Regulator of Phosphatidylcholine Metabolism, Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy  Julie Hoover-Fong,

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Presentation on theme: "Mutations in PCYT1A, Encoding a Key Regulator of Phosphatidylcholine Metabolism, Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy  Julie Hoover-Fong,"— Presentation transcript:

1 Mutations in PCYT1A, Encoding a Key Regulator of Phosphatidylcholine Metabolism, Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy  Julie Hoover-Fong, Nara Sobreira, Julie Jurgens, Peggy Modaff, Carrie Blout, Ann Moser, Ok-Hwa Kim, Tae-Joon Cho, Sung Yoon Cho, Sang Jin Kim, Dong-Kyu Jin, Hiroshi Kitoh, Woong-Yang Park, Hua Ling, Kurt N. Hetrick, Kimberly F. Doheny, David Valle, Richard M. Pauli  The American Journal of Human Genetics  Volume 94, Issue 1, Pages (January 2014) DOI: /j.ajhg Copyright © 2014 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Pedigrees of Families 1–6 Showing the Segregation of PCYT1A Mutant Alleles Alleles with the wild-type genotype indicated by plus sign. Samples were not available for individuals lacking a genotype designation. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Clinical and Radiographic Features of SMD-CRD
(A) General physical phenotype (subject 1 at age 16 years 5 months). (B) Fundus photograph showing pigmentary maculopathy (subject 3 at age 61 years). (C) Spine and pelvis radiograph demonstrating platyspondyly, characteristic pelvic configuration, and proximal femoral metaphyseal changes (subject 6 at 3 years 8 months). (D) Pelvis and femurs showing the marked metaphyseal changes that are typical (subject 4 at age 11 years 1 month). (E) Knee radiographs, similarly showing the marked metaphyseal changes that are typical in this diagnosis (subject 2 at 13 years). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

4 Figure 3 PCYT1A Structure and Domain Organization of CCTα
PCYT1A is located at 3q29 and includes ten exons (gray rectangles) as shown on the top line of the diagram. The thin rectangles encode the 5′ and 3′ UTR sequences. The right angle arrow denotes the start of the open reading frame and the asterisk indicates the location of the stop codon. The genomic coordinates on chromosome 3 are shown above. Below in color is a diagram of CCTα showing the domain structure with the diagonal dashed lines indicating the exons that contribute to each domain. The N-terminal domain (N) is in light blue with a dark blue rectangle indicating the position of the nuclear localization signal. The catalytic domain (C) is in pink. The amphitrophic membrane-binding domain (M) is in green and the C-terminal phosphorylated domain (P) is in purple. The numbers below indicate the residues at the boundaries of the domains. The mutations and their locations are shown below. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Pathways of Phosphatidylcholine Biosynthesis
Enzymes are indicated by numbers as defined below. Choline (Cho) is transported from the extracellular fluid across the plasma membrane by Na+-dependent, ATP-requiring choline transporter-like proteins (1). Free intracellular choline is phosphorylated by choline kinase (2) to produce phosphocholine (P-Cho). The latter is converted to cytidine-diphosphate choline (CDP-Cho) in a reaction catalyzed by phosphocholine cytidylyltransferase (CCTα, 3). CDP-choline is esterified with diacylglycerol (DAG) to phosphatidylcholine (PtdCho) in reactions catalyzed either by cholinephosphotransferase (4) or choline/ethanolaminephosphotransferase (5). PtdCho is converted to lyso-phosphatidylcholine (Lyso-PtdCho) by phospholipase A (6) which, in turn, is converted back to PtdCho, in a reaction catalyzed by acylglycerophosphate acyltransferase (7). In mammals, a second pathway of PtdCho synthesis is limited to liver, where PtdCho is synthesized from phosphatidylethanolamine (Ptd-Eth) in a series of methylation reactions catalyzed by phosphatidylethanolamine N-methyltransferase (8) with S-adenosylmethionine (SAM) as the methyl donor. The red rectangle indicates the position of the block in PtdCho synthesis caused by deficiency of CCT. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

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