Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

Abstract

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.

Phenotype Variability of Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease IMNEPD

“…They suffered from distal muscle weakness and delayed motor milestones, and later developed progressive ataxia and progressive cerebellar atrophy. Peripheral demyelinating sensorimotor neuropathy and endocrine abnormalities with affection of the pancreas, thyroid, and liver were furthermore present [1]. Our single-family report was rapidly further supported by a second case without detailed analysis of the disease phenotype [2].…”

“…Progressive cerebellar atrophy and ataxia imposed as key features of IMNEPD in the index family with a homozygous nonsense mutation of PTRH2. This was further underlined given the phenotype of mutant Ptrh2 mice with microcephaly and severe cerebellar atrophy [1]. However, in the light of PTRH2 missense mutationspresumably with higher residual PTRH2 levels -progressive cerebellar atrophy was present in only one patient.…”

“…As part of an integrin signaling complex, Ptrh2 regulates the fine balance between cell survival and apoptosis; it also has a role in cell size control [1,[4][5][6][7]. We recently highlighted the role of PTRH2 for human development by linking a homozygous PTRH2 gene nonsense mutation (c.269_270delCT, p.A90fs) to the disease infantile multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) [1]. Since the original description, we have identified five further patients of three consanguineous families of Tunisian and Saudi Arabian descent with an IMNEPD phenotype and a homozygous missense mutation of PTRH2 (c.254A > C, p.Q85P; Fig.…”

Bit-1 is an essential regulator of myogenic differentiation

“…Functional and physiological studies are needed in these mice to demonstrate the therapeutic potential of Bit-1 overexpression. Recently, we used whole exome sequencing to identify mutations in Bit-1 that cause progressive congenital muscle weakness in humans (Hu et al, 2014), suggesting that Bit-1 plays a key role in muscle function. Our data here point to Bit-1 as an important regulator of muscle differentiation.…”

“…Indeed, normal development is impaired in the Bit-1 nulls, as kidney subcapsular glomeruli and epaxial muscle fiber diameters are smaller than those of controls (Kairouz-Wahbe et al, 2008). Recently, we reported that a homozygous mutation in the Bit-1 gene causes infantile-onset multisystem neurologic, endocrine and pancreatic disease (IMNEPD) with corresponding muscle weakness (Hu et al, 2014). The more severely affected patient became wheelchair dependent owing to muscle weakness and ataxia by age 15.…”