Mutation of PACS1: the milder end of the spectrum

Martinez‐Monseny, Antonio; Bolasell, Mercè; Arjona, César; Martorell, Loreto; Yubero, Dèlia; Arsmtrong, Judith; Maynou, Joan; Fernàndez, Guerau; Salgado, María del Carmen; Palau, Francesc; Serrano, Mercedes

doi:10.1097/mcd.0000000000000237

Cited by 16 publications

(15 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…SHMS or PACS1 Neurodevelopmental disorder was first reported in 2012 and it is a rare cause of ID. Likely, many patients still remain unreported and, although more than 150 patients are currently known, only 61 patients have been published up to date [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 14 , 16 ]. The disease causing PACS1 variant always occurred de novo and therefore was excluded in the unaffected analyzed parents.…”

Section: Discussionmentioning

confidence: 99%

“…Most patients had anomalies in the eyes, nose, heart, and gastrointestinal system. After this first review, further patients were reported mainly from series of patients with ID evaluated through massive paralleled sequencing studies [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Remarkably, almost all patients show the same heterozygous de novo PACS1 variant c.607C > T that results in exchange of an arginine residue to a tryptophan at position 203 and is assumed to be a gain of function variant.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Tenorio

Morte

Nevado

et al. 2021

Genes

View full text Add to dashboard Cite

Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Tenorio

Morte

Nevado

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…They also delineated the clinical characteristics of all the patients and suggested that this variation in PACS1 defines a recognizable syndromic form of DD/ID and dysmorphic facial features ( Schuurs-Hoeijmakers et al, 2016 ). Subsequently, there have been sporadically reported cases with the same de novo mutation (c.607C > T) in PACS1 that caused ID and distinctive facial features ( Gadzicki et al, 2015 ; Stern et al, 2017 ; Martinez-Monseny et al, 2018 ; Pefkianaki et al, 2018 ; Wang et al, 2018 ; Dutta, 2019 ; Hoshino et al, 2019 ; Kurt Colak et al, 2020 ), except another novel variation (c.608G > A) which affects the same amino acid (Arg203; Miyake et al, 2018 ). As reviewed and reported recently, more than 50 cases with SHMS have been described in the literature, and all of them have DD/ID and dysmorphic facial features, including 51 postnatal individuals and three prenatal cases ( Kurt Colak et al, 2020 ; Lusk et al, 2020 ; Seto et al, 2020 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

et al. 2021

View full text Add to dashboard Cite

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

show abstract

“…Brain abnormalities have been found, mostly cerebellar. Other findings include ventriculomegaly, hydrocephalus or atrophy of the corpus callosum [ 3 , 5 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Clinical Characteristics Of Pacs1 -Nddmentioning

confidence: 99%

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

Arnedo

Ascaso

Latorre‐Pellicer

et al. 2022

IJMS

View full text Add to dashboard Cite

The Schuurs-Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins.

show abstract

Mutation of PACS1: the milder end of the spectrum

Cited by 16 publications

References 5 publications

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

Molecular Basis of the Schuurs–Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches

Contact Info

Product

Resources

About