PTRH2 – Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease

PTRH2 (HGNC:24265) encodes peptidyl-tRNA hydrolase 2, a mitochondrial protein involved in integrin-mediated cell survival and mTOR signaling. Biallelic PTRH2 variants underlie infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD; [MONDO:8000012]), characterized by intellectual disability, growth delay, sensorineural hearing loss, endocrine dysfunction, exocrine pancreatic insufficiency, cerebellar atrophy, ataxia, and muscle weakness.

Genetic evidence includes two affected siblings from a consanguineous family homozygous for c.269_270del (p.Ala90GlyfsTer13) (PMID:25574476), a Bahraini case with c.370del (p.Glu124LysfsTer3) (PMID:38510576), and five further probands homozygous for c.254A>C (p.Gln85Pro) (PMID:27129381). In total, eight unrelated probands across three families harbor six distinct PTRH2 alleles, including loss-of-function frameshifts and recurrent missense variants.

Inheritance is autosomal recessive, with clear co-segregation of biallelic PTRH2 mutations in one family (two affected siblings) confirming familial segregation (PMID:25574476).

Functional studies show PTRH2 is highly expressed in the developing brain and controls cell size via mTOR pathway regulation. Patient fibroblasts exhibit reduced cell survival and mTOR signaling, while global and Purkinje cell–specific Ptrh2 knockout mice recapitulate human phenotypes, including postnatal growth retardation, progressive cerebellar atrophy, ataxia, and muscle degeneration (PMID:36219306).

No conflicting evidence has been reported. The concordance of robust genetic data and multiple in vivo and cellular models supports a loss-of-function mechanism for PTRH2 in IMNEPD.

Key take-home: Biallelic PTRH2 mutations definitively cause an autosomal recessive multisystem neurologic, endocrine, and pancreatic disorder, warranting inclusion of PTRH2 in diagnostic and research gene panels for similar presentations.

References

• Annals of clinical and translational neurology • 2014 • Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. PMID:25574476
• Oman medical journal • 2024 • A Novel PTRH2 Gene Mutation Causing Infantile-onset Multisystem Neurologic, Endocrine, and Pancreatic Disease in a Bahraini Patient. PMID:38510576
• Orphanet journal of rare diseases • 2016 • Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD. PMID:27129381
• Cerebellum (London, England) • 2023 • PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients. PMID:36219306

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