Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
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ABSTRACT:
SUBMITTER: Bubshait DK
PROVIDER: S-EPMC10167404 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
Clinical and experimental pediatrics 20230323 5
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Project description:Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is a rare autosomal recessive multisystemic disease with a prevalence of < 1/1 000 000. The wide spectrum of symptoms and associated diseases makes the diagnosis of this disease particularly challenging. Here, we report a 12-year-old Bahraini male who presented with the core clinical features of IMNEPD including intellectual disability, global developmental delay, sensorineural hearing loss, endocrine dysfunction, and exocrine pancreatic insufficiency. The diagnosis was confirmed by genetic testing using whole exome sequencing. This is the first reported case of IMNEPD from Bahrain and was found to have a novel homozygous peptidyl-tRNA hydrolase 2 (PTRH2) gene mutation (NM_001015509.2: c.370del p.(Glu124Lysfs*4)). Moreover, we conducted an extensive literature review with an emphasis on the variable clinical spectrum and genotypes of previously reported patients in comparison to our case.
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Project description:Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.
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Project description:ObjectiveTo identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).MethodsWe characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts.ResultsIn a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts.InterpretationWe report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.
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