title: Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.
abstract: Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development.
authors: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
authors: Duane L
authors: DL
authors: Guernsey
authors: Haiyan
authors: H
authors: Jiang
authors: Susan C
authors: SC
authors: Evans
authors: Meghan
authors: M
authors: Ferguson
authors: Makoto
authors: M
authors: Matsuoka
authors: Mathew
authors: M
authors: Nightingale
authors: Andrea L
authors: AL
authors: Rideout
authors: Sylvie
authors: S
authors: Provost
authors: Karen
authors: K
authors: Bedard
authors: Andrew
authors: A
authors: Orr
authors: Marie-Pierre
authors: MP
authors: Dubé
authors: Mark
authors: M
authors: Ludman
authors: Mark E
authors: ME
authors: Samuels
mesh_terms: D000595:Amino Acid Sequence; D002170:Canada; D002648:Child; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011392:Proline / Q000096:biosynthesis; D011762:Pyrroline Carboxylate Reductases / Q000737:chemistry / Q000235:genetics*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D011392:Proline; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase