PPP1R21‐related syndromic intellectual disability: Report of an adult patient and review

Abstract

Variants in PPP1R21 were recently found to be associated with an autosomal recessive intellectual disability syndrome in 9 individuals. Our patient, the oldest among the known subjects affected by PPP1R21-related syndrome, manifested intellectual disability, short stature, congenital ataxia with cerebellar vermis hypoplasia, generalized hypertrichosis, ulcerative keratitis, muscle weakness, progressive coarse appearance, macroglossia with fissured tongue, and deep palmar and plantar creases. We provide an overview of the clinical spectrum and natural history of this newly recognized disorder, arguing the emerging notion that PPP1R21 gene mutations could result in endolysosomal functional defects. The oldest patients could display a more severe clinical outcome, due to accumulation of metabolites or damage secondary to an alteration of the autophagy pathway. Follow-up of patients with PPP1R21 mutations is recommended for improving the understanding of PPP1R21-related syndromic intellectual disability.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function

“…D Illustration of PPP1R21 structure including labeling of mutation site(s) on both, the nucleic acid and the amino acid (AA) level. Mutations reported previously (see references [4,7,8]) are labeled in blue whereas the pathogenic variant identified in our patient is labeled in red. Numbers in boxes refer to amino acid positions Among all upregulated proteins, the excitatory amino acid transporter 1 (P43003; ninefold increase), the cerebellar degeneration-related protein 2-like (Q86X02; sevenfold increase), the neuronal calcium sensor 1 (P62166; fivefold increased), and sacsin (Q9NZJ4; 3.8-fold increase) are particularly interesting, as they are directly related to the neuronal system.…”

“…Recent investigations describe a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss-of-function variants and imply a role for PPP1R21 within the endosomal sorting process or endosome maturation pathway [4]. So far, 11 individuals with homozygous pathogenic variants in the PPP1R21 gene have been linked to the neurological phenotype [4][5][6][7][8]. The phenotype of PPP1R21 cases shows a broad spectrum of abnormalities.…”

The novel Rab5 effector FERRY links early endosomes with the translation machinery

“…Mass spectrometry revealed the five proteins as Tbck (101 kDa), Ppp1r21 (88 kDa), C12orf4 (64 kDa), Cryzl1 (39 kDa) and Gatd1 (23 kDa) (Figure 1B). For 3 of the 5 proteins human gene mutations have been reported (Beck-Wodl et al, 2018; Bhoj et al, 2016; Chong et al, 2016; Guerreiro et al, 2016; Hancarova et al, 2019; Loddo et al, 2020; Ortiz-Gonzalez et al, 2018; Philips et al, 2017; Rehman et al, 2019; Suleiman et al, 2018; Zapata-Aldana et al, 2019). For clarity, we will refer to the novel complex as the F ive-subunit E ndosomal R ab5 and R NA/ribosome intermediar Y (FERRY) complex, with the individual subunits being designated Fy-1 – Fy-5 (Figure 1B).…”

“…Even though the FERRY complex has not previously been identified, it may play an important role in brain function. Clinical studies on patients, with a mutation in the fy-1 (tbck) or fy-2 (ppp1r21) gene, show that loss of either of these proteins severely impairs brain development and function, causing symptoms such as a mental retardation, intellectual disability, hypotonia, epilepsy, and dysmorphic facial features resulting in a premature death of the patients (Bhoj et al, 2016; Chong et al, 2016; Guerreiro et al, 2016; Hancarova et al, 2019; Loddo et al, 2020; Ortiz-Gonzalez et al, 2018; Philips et al, 2017; Suleiman et al, 2018; Zapata-Aldana et al, 2019). Different studies report the accumulation of lipofuscin the human brain and further indicate disturbances in the endocytic system (Beck-Wodl et al, 2018; Rehman et al, 2019).…”

The diagnostic utility of exome‐based carrier screening in families with a positive family history

“…Pachygyria as well as prominent ventricles have been described in affected patients, though no data are available on imaging findings immediately after birth (Loddo et al, 2020). Further follow-up will be required to confirm the diagnosis (Figure S1, Supporting Information).…”