PPM1D – Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

PPM1D encodes the wild-type p53-induced phosphatase 1 (Wip1) and is associated with Autosomal Dominant Intellectual Developmental Disorder with Gastrointestinal Difficulties and High Pain Threshold (IDDGIP) (MONDO:0044318). Affected individuals present with global developmental delay, hypotonia, short stature, feeding difficulties, high pain threshold, and variable congenital anomalies including orofacial cleft and cardiac defects.

Initial case reports described 14 unrelated patients carrying de novo truncating mutations in the last and penultimate exons of PPM1D, establishing a causal link to neurodevelopmental phenotypes (PMID:29758292). An additional patient harboring NM_003620.3:c.1535del (p.Asn512IlefsTer2) in exon 6 further corroborated the genotype–phenotype correlation, noting overlapping features such as short stature and cleft lip/palate without gastrointestinal symptoms (PMID:29758292).

Subsequent reports expanded the spectrum with a Chinese patient carrying c.1254_1255del (p.Val419GlnfsTer14) and two Taiwanese girls with c.1277dup (p.Trp427MetfsTer7), all de novo in exons 5 or 6, reinforcing the penetrant autosomal dominant inheritance and variable expressivity of JDVS (PMID:31916397; PMID:35016835).

A large retrospective cohort of 37 individuals from 34 families (including four multiplex pedigrees with autosomal dominant transmission) confirmed core manifestations: global developmental delay in 97% (35/36), hypotonia in 74% (25/34), short stature in 42% (14/33), constipation in 71% (22/31), and cyclic vomiting in 17% (6/35) (PMID:37183572). Cardiac defects were observed in at least 20% of cases, underscoring the need for multidisciplinary evaluation.

Mechanistically, truncating variants escape nonsense-mediated decay, producing a stable gain-of-function phosphatase that dephosphorylates p53 (Ser15) and γH2AX (Ser139), dampening DNA damage response and cell cycle checkpoints (PMID:16798742; PMID:20118229). iPSC-derived neurons and microglia from PPM1D+/tr lines exhibit altered proteomic and phosphoproteomic signatures implicating innate immunity, chromatin regulation, and E3 ubiquitin ligases, providing insight into neurodevelopmental and acute decompensation phenomena (PMID:37461463).

The convergence of robust de novo and familial segregation data, consistent truncating variant spectrum, and concordant functional studies support a Strong ClinGen gene–disease association. Ongoing research in cancer and clonal hematopoiesis contexts underscores the broader impact of PPM1D gain-of-function but exceeds current scoring parameters. Key Take-home: Clinicians should include PPM1D exon 5/6 truncating variants in the diagnostic workup of patients with intellectual disability, hypotonia, growth failure, and high pain threshold to inform prognosis and management.

References

• European journal of medical genetics • 2019 • Novel truncating PPM1D mutation in a patient with intellectual disability. PMID:29758292
• Molecular genetics & genomic medicine • 2020 • Novel truncating variant of PPM1D penultimate exon in a Chinese patient with Jansen-de Vries syndrome. PMID:31916397
• Journal of the Formosan Medical Association = Taiwan yi zhi • 2022 • Short stature leads to a diagnosis of Jansen-de Vries syndrome in two unrelated Taiwanese girls: A case report and literature review. PMID:35016835
• American journal of medical genetics. Part A • 2023 • Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families. PMID:37183572
• The Journal of biological chemistry • 2006 • Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. PMID:16798742
• The Journal of biological chemistry • 2010 • Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. PMID:20118229
• bioRxiv : the preprint server for biology • 2023 • Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome. PMID:37461463

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