Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy

Abstract

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum.

Figure 1

Pedigrees, PCYT1A Mutations Identified, and Protein Structure (A) Family pedigrees showing parental consanguinity and PCYT1A mutation segregation within both families, demonstrating autosomal-recessive inheritance. (B) Sequencing chromatograms showing the two different mutations found in PCYT1A: RefSeq NM_005017.2: c.385G>A (p.Glu129Lys) (family 1) and c.968dupG (p.Ser323Argfs^∗38) (family 2). (C) Schematic representation of CCT A showing the mutated residues: in family 1, a mutation was identified that alters an amino acid in the catalytic domain, and in family 2, a mutation was identified causing a premature truncation in the phosphorylation domain.

Figure 2

Clinical Images of F1.2 at 4 Months, F2.1 at 11 Years, and F1.1 at 17 Years Rhizomelic short limbs with prominent joints are evident in F1.1 and strikingly bowed lower limbs are observed in all three individuals. Radiographs of F1.2 (7-month-old girl), F2.1 (11-year-old girl), and F1.1 (17-year-old boy): profile and anteroposterior (AP) views of the spine; AP view of the pelvis; AP view of the lower limbs; AP view of the upper limbs; AP view of the hands. Note the platyspondyly associated with ovoid vertebral bodies (F1.2) and anterior wedging (F2.1). Scoliosis may develop in older individuals (F1.1). A narrow sacrosciatic notch (F1.2) and coxa vara (F2.1 and F1.1) are disclosed in the pelvis. There is a generalized shortening of the long bones with widened and irregular metaphyses. Lateral and medial spurs in the distal femur with enlarged epiphyses are evident in F2.1. Progressive bowing deformity in the lower legs is striking. Mildly shortened metacarpals and phalanges are observed in all individuals.

Figure 3

Ophthalmological Evaluation of F2.2 and F1.1 Shown are retinography (A), OCT (B), and full-field ERG (C). In the retinography, F2.2 presents only decreased macular brightness and mild pigmentary changes in the fovea bilaterally (A1). Despite this mild phenotype, decreased macular thickness is evident in the OCT (B), and there is a severely reduced photopic response in ERG with the scotopic response being at the lower limit of normality (C1). A severe phenotype with vascular narrowing, and RPE and macular atrophy (A2, top) is associated with eye malformations (coloboma of the optic nerve) in F1.1 (A2, bottom). No electrical activities were detectable in the full-field ERG (C2).