Reversade B et al. (2009), Mutations in PYCR1 cause cutis laxa with proger...

XB-ART-40177

Nat Genet 2009 Sep 01;419:1016-21. doi: 10.1038/ng.413.

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Mutations in PYCR1 cause cutis laxa with progeroid features.

Reversade B , Escande-Beillard N , Dimopoulou A , Fischer B , Chng SC , Li Y , Shboul M , Tham PY , Kayserili H , Al-Gazali L , Shahwan M , Brancati F , Lee H , O'Connor BD , Schmidt-von Kegler M , Merriman B , Nelson SF , Masri A , Alkazaleh F , Guerra D , Ferrari P , Nanda A , Rajab A , Markie D , Gray M , Nelson J , Grix A , Sommer A , Savarirayan R , Janecke AR , Steichen E , Sillence D , Hausser I , Budde B , Nürnberg G , Nürnberg P , Seemann P , Kunkel D , Zambruno G , Dallapiccola B , Schuelke M , Robertson S , Hamamy H , Wollnik B , Van Maldergem L , Mundlos S , Kornak U .

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Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

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Species referenced: Xenopus
Genes referenced: pycr1 tal1
GO keywords: proline metabolic process [+]
???displayArticle.morpholinos??? Pycr1 MO1

???displayArticle.disOnts??? autosomal recessive cutis laxa type IIB
???displayArticle.omims??? CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIB; ARCL2B

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	Figure 4 - Phenotype of Pycr1 Xenopus morphants. (a) Pycr1 is evolutionary conserved among bacteria, plants, insects and vertebrates. (b) Design of a translation-blocking morpholino (MO) oligonucleotide for Xenopus Pycr1. (c) Control embryo at stage 30. (d) Pycr1 morphants injected in each blastomere at the four-cell stage failed to grow a tail and had underdeveloped eyes. (e) Dorsal (D) MO injections impaired eye but not tail development. (f) Ventral (V) MO injections impaired tail but not eye development. Arrowheads, skin wrinkles. (g) Control embryo at the swimming tadpole stage. (h) Pycr1 morpholino-injected embryos showing severe growth retardation and large regions of ectodermal edema over the entire body, which develop from wrinkles seen earlier (e,f). (i) Histological section of skin from control embryo at stage 45 showing bilayered epidermis consisting of outer periderm and inner sensorial layer. (j) Disorganized architecture of epidermis with enlarged cells, enlarged nuclei and cellular protrusions in Pycr1 morphant. Image redisplayed with permission from Macmillan Publishers Ltd.
	Figure 5 - Skin hypoplasia in Pycr1 morphants is accompanied by spontaneous apoptosis and is independent of anemia. (a) Scl expression at stage 25 marks site of primitive hematopoiesis in ventral ectoderm of control embryo. (b) Scl expression was abrogated in Pycr1 morphants suffering anemia (Supplementary Videos 1 and 2). (c) Parabiosis performed at stage 22 between a Pycr1-depleted (MO) tadpole (top) and control (bottom) did not rescue from apoptosis (inset, stage 33), stunted growth and skin defects despite shared blood circulation (Supplementary Video 3). (d) Histological staining. Epidermis of Pycr1 parabiotic morphant embryo remained disorganized relative to control. (e) Histological section through epidermis of parabiotic control tadpole at stage 45 showing normal skin architecture. (f) Acridine-orange background staining of control embryo (inset, bright-field image). (g) Acridine-orange labeling of dying cells (intense green) in Pycr1 morphant embryos injected only in the ventral (V) half (inset, bright-field image). Only the ventro-posterior half of the embryo, derived from the injected ventral blastomeres, is undergoing apoptosis. (h) TUNEL staining in stage 33 tadpole showing few apoptotic cells (inset, control at stage 25). (i) Pycr1 morphants, with a markedly increased number of dying cells at stage 33 relative to control (inset, stage 25). Image redisplayed with permission from Macmillan Publishers Ltd.
	Figure 1.Figure 1: Phenotypic characteristics and genetic findings of subjects with PYCR1-related autosomal recessive cutis laxa with progeroid appearance. (a) Affected 2-year-old girl from family T.P., initially diagnosed with wrinkly skin syndrome. (b) Affected 18-month-old girl from family D.I. clinically categorized as having gerodermia osteodysplastica. (c) Newborn boy from family E.U. diagnosed with de Barsy syndrome. Typical facial gestalt including triangular face, malar hypoplasia and dysplastic, large ears. (d) Skin wrinkling at the dorsum of the hand and typical adducted thumb in an affected individual from family H.B. Participants gave consent for publication of all photos. (e–h) Findings in skin biopsy from affected individual from family D.I. (e,f) Weigert staining reveals sparse, thinned and fragmented elastic fibers in the reticular dermis compared to control (f); scale bar, 100 mum. (g,h) Ultrastructural analyses corroborate the markedly reduced elastic fiber (arrows) size with a reduction in both the fibrillar and amorphous components in an affected individual from family D.I. compared to control (h); scale bar, 500 nm. (i) Homozygosity mapping resulted in a minimal candidate region of 2.8 Mb on chromosome (chr.) 17q25 between markers rs8065431 and rs1046896. Only the four most informative pedigrees are shown. (j) Genomic capture followed by next-generation sequencing of the maximal candidate region extending from 72.05–78.77 Mb. A sequence change of C>T was sequenced seven times in a subject from family G.O. This base change resulted in a single R119H substitution in PYCR1.
	tal1(T-cell acute lymphocytic leukemia 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 27, lateral view, anterior left, dorsal up., and ventral view, anterior up, to right)

References [+] :

Abecasis, Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. 2002, Pubmed