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.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

“…During the course of our study, two independent manuscripts described the identification of biallellic PCYT1A mutations in eight unrelated probands with severe short stature due to spondylometaphyseal dysplasia and visual impairment due to cone-rod retinal dystrophy (21,22). All affected individuals presented with severe skeletal manifestations early in childhood, whereas the retinal phenotype was considerably more variable in onset.…”

“…All affected individuals presented with severe skeletal manifestations early in childhood, whereas the retinal phenotype was considerably more variable in onset. Most of their patients were not carefully assessed for the presence of lipodystrophy and/or metabolic disease, but in a few cases liver ultrasounds did not reveal significant hepatic steatosis (22). Neither report formally characterized the biochemical impact of the mutations but many of the mutations, which spanned all of the known functional domains of PCYT1A, besides the extreme N-terminal nuclear localization domain, were strongly predicted to be damaging.…”

CTP:phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis

“…In humans, however, single nucleotide changes in PCYT1A that inhibit enzyme activity have been linked to two human diseases with differing phenotypic manifestation: Spondylometaphyseal Displasia with Cone-Rod Dystrophy (SMD-CRD; [259,260]); and lipodystrophy [261]. Individuals affected by both disorders are bi-allelic, and were homozygous or mixed heterozygous, suggesting that disease does not arise if there is one wild-type copy of PCYT1A.…”

Choline‐related‐inherited metabolic diseases—A mini review

“…This is the key rate‐limiting step performed by choline‐phosphate cytidyltransferase A (PCYT1A, PCYT1A ), which is ubiquitously expressed, and by choline‐phosphate cytidyltransferase B (PCYTB) expressed in selected tissues. Biallelic variants in PCYT1A have been associated with cone‐rod dystrophy, either isolated or in combination with spondylometaphyseal dysplasia (MIM#123695) . Additionally, congenital lipodystrophy, fatty liver, severe insulin resistance, and diabetes were seen in two patients, providing evidence for an additional and essential role of PCYT1A‐generated PC in the normal function of white adipose tissue and insulin action .…”