Disruption of PTPS Gene Causing Pale Body Color and Lethal Phenotype in the Silkworm, Bombyx mori.

Xiaoling Tong,Yuanhao Li,Pingfeng Liang,Songyuan Wu,Zhonghuai Xiang,Liang Qiao,Cheng Lu,Fangyin Dai,Hai Hu

doi:10.3390/ijms19041024

Xiaoling Tong, Yuanhao Li + Show 7 more

Open Access

https://doi.org/10.3390/ijms19041024

Copy DOI

Abstract

Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene or by defects in the tetrahydrobiopterin (BH4) synthesis pathway. Here, by positional cloning, we report that the 6-pyruvoyl-tetrahydropterin synthase (PTPS) gene, encoding a key enzyme of BH4 biosynthesis, is responsible for the alc (albino C) mutation that displays pale body color, head shaking, and eventually lethality after the first molting in silkworm. Compared to wild type, the alc mutant produced more substrates (phenylalanine (Phe) and tyrosine (Tyr)) and generated less DOPA and dopamine. Application of 2,4-diamino-6-hydroxypyrimidine (DAHP) to block BH4 synthesis in the wild type effectively produced the alc-like phenotype, while BH4 supplementation rescued the defective body color and lethal phenotype in both alc and DAHP-treated individuals. The detection of gene expressions and metabolic substances after drugs treatments in alc and normal individuals imply that silkworms and humans have a high similarity in the drugs metabolic features and the gene pathway related to BH4 and the dopamine biosynthesis. We propose that the alc mutant could be used as an animal model for drug evaluation for BH4-deficient PKU.

Highlights

Phenylketonuria (PKU; OMIM 261600) is an inherent disorder of metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, which results in the accumulation of phenylalanine (Phe)
Based on the functional annotation of the 18 genes and the biological processes these may be involved in, the present study focused on one gene, BGIBMGA003643, which encodes 6-pyruvoyl-tetrahydropterin synthase (PTPS), a key enzyme in BH4 metabolism (Figure 2A)
The responsible gene for larval pigmentation, alc, was determined to encode PTPS, which is a key enzyme of BH4 biosynthesis

Summary

Introduction

Phenylketonuria (PKU; OMIM 261600) is an inherent disorder of metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, which results in the accumulation of phenylalanine (Phe). PAH associates with a native co-factor tetrahydrobiopterin (BH4) that hydroxylates Phe to tyrosine (Tyr) (Supplementary Figure S1A). Defects in either PAH or BH4 synthesis may result in hyperphenilalaninemia, which can cause intellectual disability when untreated [1]. Phenylketonuria may result in progressive irreversible neurological impairment during infancy and childhood when not detected and treated in a timely manner. The most common symptom is severe mental retardation, which is often coupled with a musty odor in their breath, skin, and urine, eczema, reduced melanin pigmentation, growth retardation, depressive and anxiety disorders, and epilepsy. The severity of the clinical phenotype is directly correlated to blood phenylalanine levels [2]

Methods

Results

Conclusion