PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus

Abstract

Prolyl endopeptidase-like (PREPL) deficiency (MIM 616224) is a very rare congenital disorder characterized by neonatal hypotonia and feeding difficulties, ptosis, neuromuscular symptoms, cognitive impairments, growth hormone deficiency, short stature, and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene. Previous reports have associated PREPL deficiency with only one nucleotide substitution, the deletion of four nucleotides, and eight small microdeletions in the PREPL gene In this study, we used whole exome sequencing (WES) to identify a novel homozygous splicing mutation (c.616 + 1G > T) in a 14-year-old Chinese girl with PREPL deficiency. Sequencing of the RT-PCR products from the patient's blood sample revealed that the c.616 + 1G > T variant disrupted normal splicing in intron 4 leading to an aberrant inclusion of 43 nucleotides in intron, a frameshift, and premature termination codon. Our patient exhibited several of the common phenotypes, including severe neonatal hypotonia, growth impairment and cognitive problems. However, we also observed several unusual phenotypic characteristics: absence of the ovaries, hypoplasia of the uterus, microcephaly and a short neck in patient is alsoobserved. These results provide further evidence for the involvement of PREPL development of the ovaries and uterus. Our findings may provide further insight into the relationship between the genotype and phenotype in collagen-associated diseases and improve the clinical diagnosis of Prolyl endopeptidase-like deficiency.

Genome-wide screens for mitonuclear co-regulators uncover links between compartmentalized metabolism and mitochondrial gene expression

“…S7 ). To directly test the possibility of a transcriptional defect in NME6 KO cells, we pulse-labeled newly synthesized RNAs in purified mitochondria with 32 P-UTP and visualized newly transcribed RNA with denaturing-PAGE and autoradiography ( Fig. S8 ).…”

“…Supplementary Figure 8. In organello mitochondrial transcription visualized by 32 P-UTP labeling in purified mitochondria. RNA was visualized using TBE-urea PAGE, followed by autoradiography of newly synthesized mt-RNA.…”

“…PREPL (prolyl-endopeptidase like) is a human disease gene of unknown function, in which mutations cause congenital myasthenic syndrome [28][29][30][31][32][33] . We found that deletion of PREPL in K562 cells caused a reduction in mitochondrial-encoded COX1 while nuclear-encoded COX4 remained near wild-type levels.…”

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

“…The PREPL deficiency is characterized by severe neonatal hypotonia, muscular weakness, feeding problems, and growth failure. To date, only about 10 patients with isolated PREPL deficiency were reported [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. The affected patients also have facial dysmorphism, motor developmental delay, and urogenital anomalies, as in our patient.…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…PREPL- CMS without pathogenic variants SLC3A1 has been reported in 11 patients since 2014 [ 33 , 351 , 370 , 371 , 372 , 373 , 374 , 375 , 376 ]. Similarly, PREPL- CMS with SLC3A1 deletion, the diagnosis of which is HCS, has been reported in 7 patients since 2014 [ 33 , 351 ].…”