Genetic Variation in Phenylalanine Protein Linked to Weight Gain in PKU Infants

Genetic Variation in Phenylalanine Protein Linked to Weight Gain in PKU Infants

A specific variation in a gene associated with phenylalanine transport is strongly linked to weight gain and an increased risk of obesity in infants with phenylketonuria (PKU), a recent study shows.

The findings have implications for the management of PKU in children, as patients carrying these gene variants should receive different treatment protocols to avoid excessive weight gain, the researchers said.

The study, “Carriership of the rs113883650/rs2287120 haplotype of the SLC7A5 (LAT1) gene increases the risk of obesity in infants with phenylketonuria,” was published in the journal Molecular Genetics and Metabolism Reports.

PKU is a rare genetic disorder in which patients cannot digest the essential amino acid phenylalanine due to a mutation in the gene that codes for the protein phenylalanine hydroxylase (PAH).

The severity of PKU is often related to the number of functional copies of the PAH gene. Patients with one healthy copy of PAH will retain some level of phenylalanine digestion, and can have milder symptoms.

However, because of diversity across patient populations, information about PAH genetics alone does not necessarily predict phenylalanine metabolism.

Some patients who strictly follow low-phenylalanine diets still develop obesity, and levels of phenylalanine in the blood may not correspond to recent phenylalanine consumption in some individuals.

To determine other factors that may predict PKU symptom severity, a team of Polish researchers set out to study genetic variations in other proteins associated with phenylalanine metabolism.

The team selected a total of 10 genes that code for proteins associated with phenylalanine, specifically those involved in phenylalanine transport, and those involved in PAH-independent phenylalanine metabolism.

The genes were sequenced in a total of 100 infants — 47 girls and 53 boys — born between 2000 and 2018, who were patients at five metabolic pediatric centers associated with the Jagiellonian University Medical College in major regions across Poland.

Only patients who did not have any functional copies of the PAH gene were included in the study, to ensure that symptom variations were caused by other factors.

The study investigated two main symptoms in the infants with PKU: obesity and daily phenylalanine tolerance, or the amount of phenylalanine a person can consume while maintaining levels of phenylalanine in the blood within the recommended range.

Obesity was measured by taking height and weight measurements of the infants after birth, at six months, and at one year, to calculate body mass index (BMI).

The results showed that the infants’ BMI was collectively higher than average at both six months and one year. The values for girls were 17.84 at six months and 18.32 at one year, while those for boys were 18.36 at six months and 18.38 at one year.

To monitor diet and daily phenylalanine tolerance, a dietitian was assigned to design a low-phenylalanine diet that still provided approximately 2.4 g of daily protein consumption per 1 kg of body weight.

This dietary plan ensured that the infants maintained a blood level of phenylalanine between 0.12–0.36 mmol/L, the recommended range.

The researchers found that the daily phenylalanine tolerance was 138 mg when the low-phenylalanine diet was first initiated (within the first month of life), increased to 275 mg at six months and stayed relatively constant at 278 mg at one year.

Also, while 29% of the infants were breastfed, compared with 71% receiving formula as their source of natural protein, no differences were associated with the two modes of feeding.

Looking at the genetics, the researchers isolated a total of 34 genetic variants from the 10 genes of interest in the study.

From these variants, one particular variation in the SLC7A5 gene — named rs113883650/rs2287120 for two mutations that are mutually inherited — was correlated with a highly significant increase in weight at six months.

The SLC7A5 gene codes for the L-type amino acid transporter 1 protein, which is involved in the transport of phenylalanine across cellular membranes.

When measurements were taken at the age of six months, girls with the SLC7A5 variation had an average BMI of 19.1 compared with 17.39 in those without the variation; the difference was 19.39 compared with 18 in boys.

The study did not find any significant changes in daily phenylalanine tolerance associated with any of the genetic variations. Also, energy and total protein intake was no different in patients with and without the SLC7A5 variation.

Ultimately, the findings led the team to conclude that the rs113883650/rs2287120 SLC7A5 variation in PKU patients is linked to a higher magnitude of weight gain. The researchers proposed making dietary changes to compensate for this connection.

“Our study demonstrates a clinically relevant association between developing overweight in patients with PKU and the carriership of the common rs113883650/rs2287120 haplotype of the SLC7A5 gene encoding the L-type amino acid transporter 1,” they wrote.

“Our findings might have potential practical implications for children with PKU, since treatment protocols need to be reassessed to better prevent overweight in the carriers of the above gene variant,” the team concluded.

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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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