title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
abstract: Autosomal recessive cutis laxa type 2B (ARCL2B; OMIM # 612940) is a segmental progeroid disorder caused by mutations in PYCR1 encoding pyrroline-5-carboxylate reductase 1, which is part of the conserved proline de novo synthesis pathway. Here we describe 33 patients with PYCR1-related ARCL from 27 families with initial diagnoses varying between wrinkly skin syndrome, gerodermia osteodysplastica, De Barsy syndrome or more severe progeria syndromes. Given the difficult differential diagnosis of ARCL syndromes we performed a systematic comparison of clinical features of PYCR1-related ARCL. Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects. Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value. In our cohort we identified 20 different PYCR1 mutations of which seven were novel. Most of the mutations accumulated in exons 4 to 6. Missense alterations of highly conserved residues were most frequent followed by splice site changes and a single nonsense mutation. Analysis of genotype-phenotype correlation revealed that patients with mutations in the first two exons had lower average clinical scores and absent or only mild intellectual disability. Structural analyses predicted interference with PYCR1 multimerization for a subset of missense mutations. These findings have implications for the clinics as well as the pathomechanism of PYCR1-related ARCL.
authors.affiliation: Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Dimopoulou
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer
authors.forename: Thatjana
authors.initials: T
authors.lastname: Gardeitchik
authors.forename: Phillipe
authors.initials: P
authors.lastname: Schröter
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Claire
authors.initials: C
authors.lastname: Schlack
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Jaime Moritz
authors.initials: JM
authors.lastname: Brum
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Barisic
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.forename: Christiane
authors.initials: C
authors.lastname: Spaich
authors.forename: Elaine
authors.initials: E
authors.lastname: Fletcher
authors.forename: Zeina
authors.initials: Z
authors.lastname: Mahayri
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Bhat
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
authors.forename: Katherine
authors.initials: K
authors.lastname: Lachlan
authors.forename: Diana
authors.initials: D
authors.lastname: Johnson
authors.forename: Shubha
authors.initials: S
authors.lastname: Phadke
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.forename: Martina
authors.initials: M
authors.lastname: Simandlova
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
mesh_terms: D000483:Alleles; D003483:Cutis Laxa / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons; D019066:Facies; D023061:Gene Order; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D011762:Pyrroline Carboxylate Reductases / Q000737:chemistry / Q000235:genetics*; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
keywords: Autosomal recessive cutis laxa; Mitochondria; PYCR1; Proline; Segmental progeroid disorders