PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Alhaddad, Bader; Schossig, Anna; Haack, Tobias B.; Kovács-Nagy, Réka; Braunisch, Matthias C.; Makowski, Christine; Senderek, Jan; Vill, Katharina; Müller‐Felber, Wolfgang; Strom, Tim M.; Krabichler, Birgit; Freisinger, Peter; Deshpande, Charu; Polster, Tilman; Wolf, Nicole I.; Desguerre, Isabelle; Wörmann, F.; Rötig, Agnès; Ahting, Uwe; Kopajtich, Robert; Prokisch, Holger; Meitinger, Thomas; Feichtinger, René G.; Mayr, Johannes A.; Jungbluth, Heinz; Hubmann, Michael; Zschocke, Johannes; Distelmaier, Felix; Koch, Johannes

doi:10.1055/s-0038-1661396

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…In this context, the electroencephalogram (EEG) documents variable discharges, progressive development of hypsarrythmia, and/or slowed background activity as the epileptic encephalopathy worsens. Furthermore, vision problems such as optic atrophy, esotropia, cortical blindness, bilateral rudimentary iris strands, congenital cataracts, saccadic eye movements, and nystagmus have been reported and are often present after birth ( 1 , 8 , 13 , 19 , 20 , 23 ). Recently, gastrointestinal disorders such as dysphagia and gastrointestinal reflux have been described, usually followed by inadequate oral caloric intake and failure to thrive, requiring nasogastric tube feeding or gastrotomy tube placement ( 1 , 13 , 20 ).…”

Section: Clinical Featuresmentioning

confidence: 99%

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Scorrano,

Battaglia,

Spiaggia

et al. 2023

Front. Neurol.

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Prune exopolyphosphatase 1 (PRUNE1) is a short-chain phosphatase that is part of the aspartic acid-histidine-histidine (DHH) family of proteins. PRUNE1 is highly expressed in the central nervous system and is crucially involved in neurodevelopment, cytoskeletal rearrangement, cell migration, and proliferation. Recently, biallelic PRUNE1 variants have been identified in patients with neurodevelopmental disorders, hypotonia, microcephaly, variable cerebral anomalies, and other features. PRUNE1 hypomorphic mutations mainly affect the DHH1 domain, leading to an impactful decrease in enzymatic activity with a loss-of-function mechanism. In this review, we explored both the clinical and radiological spectrum related to PRUNE1 pathogenic variants described to date. Specifically, we focused on neuroradiological findings that, together with clinical phenotypes and genetic data, allow us to best characterize affected children with diagnostic and potential prognostic implications.

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Section: Clinical Featuresmentioning

confidence: 99%

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Scorrano,

Battaglia,

Spiaggia

et al. 2023

Front. Neurol.

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“…A different mutation in the splice donor site within intron 2 of the PRUNE_1 gene (i.e., c.132+2T>C) was also described in five patients from two consanguineous Sudanese families (50). Moreover, homozygous deletion (g.1509-84457-151016-662del) starting from exon 2 to exon 8 including the 3′UTR was also found in two female children from Austria (16). Similarly, a homozygous truncating c.50dup (p.Leu18Serfs*8) variant was found in a Japanese child (17).…”

Section: Recessive Mutations In Prune_1 Locus Are Responsible For Nddmentioning

confidence: 87%

“…To date, 64 patients carrying different mutations in the PRUNE_1 gene have been reported worldwide (Figure 1 and Table 1). Regarding the genotypic differences, among the variants identified in patients with PRUNE_1, the most representative was the homozygous c.G316A (p.D106N) variant that was found in 15 subjects: seven from Turkey (12,16,18), three from Italy (10,14), one from Sri Lanka (19), one from Caucasus (17), and three from Lebanon (16). The majority of homozygous mutations were found within the DHH domain of PRUNE_1, including c.G88A (p.D30N) in six patients from Oman (10) and one from Saudi Arabia (12), c.160C>A (p.P54T) in seven Iranian subjects (10), c.383G>A (p.R128Q) in two patients from Saudi Arabia (15), and c.515T>C (p.L172P) in three children from North Africa (16).…”

Section: Recessive Mutations In Prune_1 Locus Are Responsible For Nddmentioning

confidence: 99%

“…Regarding the genotypic differences, among the variants identified in patients with PRUNE_1, the most representative was the homozygous c.G316A (p.D106N) variant that was found in 15 subjects: seven from Turkey (12,16,18), three from Italy (10,14), one from Sri Lanka (19), one from Caucasus (17), and three from Lebanon (16). The majority of homozygous mutations were found within the DHH domain of PRUNE_1, including c.G88A (p.D30N) in six patients from Oman (10) and one from Saudi Arabia (12), c.160C>A (p.P54T) in seven Iranian subjects (10), c.383G>A (p.R128Q) in two patients from Saudi Arabia (15), and c.515T>C (p.L172P) in three children from North Africa (16). Two types of homozygous mutations were also found within the DHHA2 domain: the missense variant c.C889T (p.R297W) in two patients from India (10) and the frameshift variant c.874_875insA (p.H292Qfs*3) in one subject from Turkey (52).…”

Section: Recessive Mutations In Prune_1 Locus Are Responsible For Nddmentioning

confidence: 99%

“…Furthermore, recessive mutations in PRUNE_1 locus (1q21.3) were also identified as candidate genetic causes of neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; MIM #617481) (10,(12)(13)(14)(15)(16)(17)(18)(19)(20). Similarly, other genes responsible for microcephaly (MCPH) and mainly implicated in cell division mechanisms were also found both overexpressed in brain tumors (i.e., MB) and mutated in neurodevelopmental disorders (NDDs).…”

Section: Introductionmentioning

confidence: 99%

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Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors

et al. 2021

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We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.

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PRUNE1 c.933G>A synonymous variant induces exon 7 skipping, disrupts the DHHA2 domain, and leads to an atypical NMIHBA syndrome presentation: Case report and review of the literature

Magyar

Murdock

Burrage

et al. 2022

American J of Med Genetics Pt A

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Prune exopolyphosphatase‐1 (PRUNE1) encodes a member of the aspartic acid–histidine–histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss‐of‐function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1‐related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6‐year‐old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in‐frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH‐associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1‐related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.

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PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Abstract: deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

Cited by 11 publications

References 19 publications

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Neuroimaging in PRUNE1 syndrome: a mini-review of the literature

Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors

PRUNE1 c.933G>A synonymous variant induces exon 7 skipping, disrupts the DHHA2 domain, and leads to an atypical NMIHBA syndrome presentation: Case report and review of the literature

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