title: Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities.
abstract: Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained.
authors.affiliation: Division of Metabolism, Kinderspital Zurich, Pediatric Research Centre, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
authors.forename: Rita
authors.initials: R
authors.lastname: Kretz
authors.forename: Bita
authors.initials: B
authors.lastname: Bozorgmehr
authors.forename: Mohamad Hasan
authors.initials: MH
authors.lastname: Kariminejad
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000172:deficiency* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004549:Elastin / Q000172:deficiency* / Q000378:metabolism; D005190:Family; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D020125:Mutation, Missense; D010641:Phenotype; D011392:Proline / Q000096:biosynthesis / Q000172:deficiency*; D011758:Pyrroles / Q000378:metabolism; D011762:Pyrroline Carboxylate Reductases / Q000172:deficiency / Q000235:genetics*; D055815:Young Adult; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D003094:Collagen; D004549:Elastin; D011392:Proline; D011758:Pyrroles; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C015485:delta-1-pyrroline-5-carboxylate