The PYCR1 enzyme consists of 319 amino acids and has a size of about 33 kDa. It forms a homopolymer and localizes to the mitochondrion. The enzyme catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline and also plays a physiologic role in the generation of NADP(+) in some cell types. It has two transcript variants encoding different isoforms due to the alternate splicing of its encoding gene.
The PYCR1 gene is located on chromosome 17q25.3. It has eight coding exons and spans 10 kb in length. Mutations in PYCR1 are the cause of cutis laxa autosomal recessive type 2B, characterized by abnormal growth, developmental delay, and associated skeletal abnormalities.
Reversade et al. (2009) carried out mutation analysis for the PYCR1 gene in Bahraini patients affected with ARCL2. The c535G>A mutation was detected. The mutation is predicted to cause a p.A179T amino acid substitution in the resulting protein.
[See: Syria > Dimopoulou et al., 2013].
In affected members of a Jordanian family with intrauterine growth retardation, cutis laxa, hernias, abnormal corpus callosum, and mental retardation, and a Syrian patient with intrauterine growth retardation, cutis laxa, hernias, osteopenia, agenesis of the corpus callosum, and mental retardation, Reversade et al. (2009) identified homozygosity for a splice site deletion (797+2_797+5del) in intron 6 of the PYCR1 gene, predicted to result in K215_D319del. Analysis of skin fibroblasts from one of the affected Jordanian individuals revealed strongly reduced PYCR1 protein levels.
In three children with intrauterine growth retardation, cutis laxa, hip dislocation, hernias, osteopenia, and mental retardation from two unrelated consanguineous Kuwaiti families, Reversade et al. (2009) identified homozygosity for a 797G>A transition in exon 6 of the PYCR1 gene, resulting in an arg266-to-gln (p.R266Q) substitution predicted to affect splicing by altering the invariable donor splice site at the 3-prime end of exon 6.
In three sibs from a consanguineous Omani family with congenital cutis laxa, bowing of the long bones, multiple fractures due to osteopenia, and mental retardation, Reversade et al. (2009) identified homozygosity for a 356G>A transition in exon 4 of the PYCR1 gene, resulting in an arg119-to-his (p.R119H) substitution.
In three Palestinian sibs with intrauterine growth retardation, cutis laxa, hip dislocation, osteopenia, mild abnormalities of the corpus callosum, and mild mental retardation, born of first-cousin parents, Reversade et al. (2009) identified homozygosity for a 22-bp deletion (617_633+6del) encompassing the exon-intron boundary of exon 5 of the PYCR1 gene. In a Palestinian girl, they have also identified homozygosity for a 616G>T transversion in exon 5 of the PYCR1 gene, resulting in a gly206-to-trp (p.G206W) substitution. Analysis of skin fibroblasts revealed a reduction in protein abundance relative to control cells.
Reversade et al. (2009) reported a c.616G>A mutation in the PYCR1 gene in a Qatari family with ARCL2 disorder. The mutation is predicted to cause a p.G206R amino acid substitution in the resulting protein.
Al-Owain et al. (2012) reported the case of a Saudi girl with De Barsy syndrome. The patient was born full term to healthy consanguineous parents. Sequencing of the PYCR1 gene revealed the presence of a homozygous missense mutation, c.616A>G, that results in a p.G206R substitution.
Dimopoulou et al. (2013) described 33 patients with ARCL2, of which three were from Syria and one from Iraq. The Syrian patients were found to have homozygous splice site mutations at exon 4 of PYCR1 gene. The Iraqi patient had a homozygous p.Ala179Thr mutation at exon 4.
[See also: Jordan > Reversade et al., 2009].