Loss of PCLO function underlies pontocerebellar hypoplasia type III

Ahmed, Mustafa Y; Chioza, Barry A.; Rajab, Anna; Schmitz-Abe, Klaus; Al-Khayat, Aisha; Al-Turki, Saeed; Baple, Emma L.; Patton, Michael A.; Al-Memar, A; Hurles, ME; Partlow, Jennifer N.; Hill, Robert S.; Evrony, Gilad D.; Servattalab, Sarah; Markianos, Kyriacos; Walsh, Christopher A.; Crosby, Andrew H.; Mochida, Ganeshwaran H.

doi:10.1212/wnl.0000000000001523

Cited by 52 publications

(42 citation statements)

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“…The Pclo SBΔ4-25 rat model exhibited additional GABAergic neuropathies. Both homozygous and heterozygous Pclo SBΔ4-25 rats develop generalized seizures (Fig 6A), similar to seizures observed in children homozygous for Pclo Δ6-stop of pontocerebellar hypoplasia type 3a [18]. Disturbed GABAergic synaptic transmission in Pclo mutants likely affects the balance between inhibition and excitation and thereby provokes seizures, manifesting itself as epileptiform activity [34,35].…”

Section: Discussionsupporting

confidence: 60%

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Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Medrano

Singh

Plautz

et al. 2018

Preprint

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Successful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Atg13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive.Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction. Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact one's emotions, including depression and bipolar disorder.Although studies in human populations implicate changes to Piccolo's DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutationdependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.pathologies, and in males, Atg13 gt/gt was further complicated with abnormal spermatozoa. Thus, the cause of infertility of Atg13 gt/gt rats is a cumulation of general fitness problems. Compromised neurotransmission in Pclo mutantsDespite their reproductive failure (Fig 2A), Pclo gt/gt mutant rats did not display any obvious dysfunction during gametogenesis (S2A and S2C Fig). Numbers of epididymal spermatozoa from Pclo gt/gt rats were relatively normal (Fig 2C). However, spermatozoa from Pclo gt/gt rats were not found in vaginal swabs of WT females (6 of 6 breeder pairs) (Fig 4A, and spermatozoa from WT males were not detected in Pclo gt/gt females (6 of 6 breeder pairs) (Fig 4A), suggesting that the mating did not actuall...

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Section: Discussionsupporting

confidence: 60%

“…Among the reproduction genes, we identified Atg13, which has generally been connected to longevity in species ranging from yeast to plants and humans. We also identified phenotypes in Pclo-deficient (Pclo gt/gt ) rats that hold potential to model humans diagnosed with neurological disorders [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Medrano

Singh

Plautz

et al. 2018

Preprint

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“…Our findings, together with previous biological evidence (Ahmed et al, 2015;Waites et al, 2011), suggest the importance of the PCLO gene to MDD, which is worth further replication and functional studies.…”

Section: Twin Research and Human Geneticssupporting

confidence: 79%

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

et al. 2017

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In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10 −8 ) and gene-based (p = 1.48 × 10 −7 ) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.Keywords: major depressive disorder, genome-wide association study, genetics, PCLO In 2009, as part of the Genetic Association Information Network (GAIN) initiative, we published (Sullivan et al., 2009) the first genome-wide association study (GWAS) for major depressive disorder (MDD). The participants were assembled from two large Dutch cohorts: the Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Registry (NTR). A comparison between 1,738 cases with lifetime diagnosis of DSM-IV MDD and 1,802 screened controls highlighted a signal overlapping the region of PCLO gene, although variants identified did not reach genome-wide significance. Importantly, our result received strong support (though not reaching formal significance) from Australian data similarly ascertained from a population twin registry (Sullivan et al., 2009). Based on the promising role of PCLO encoding a cytoskeletal protein located in the presynaptic active zone, the original finding was followed by replication efforts, with positive (Hek et al., 2010) and negative (Verbeek et al., 2013) results. In the present study, we revisited the original GWAS after introducing important improvements. The overall sample size was almost doubled, adding newly genotyped participants from the original cohorts, consisting mainly of a large number of controls carefully screened using several sources of information including longitudinal assessments and family history (Boomsma et al., 2008). The number of interrogated SNPs was increased by re-genotyping the majority of participants on a newer array and by imputing variants with a denser reference panel (1,000 Genomes Phase 3).The present sample consisted of 6,507 participants (63.1% females) of European ancestry from NESDA and NTR. Lifetime MDD diagnoses according to DSM-IV were ascertained using the Composite Interview Diagnostic Instrument. Healthy controls were screened based on absence of any lifetime psychiatric disorder (NESDA), no report of MDD, no known first-degree relatives with MDD, and a low factor score based on a multivariate analysis of depressive complaints, anxiety, neuroticism, and somatic anxiety (Boomsma et al., 2000). After applying stringent quality control criteria (Supplementary Methods), we performed a GWAS comparing 1,942 cases and 4,565 controls, 267https://www.cambridge.org/core/terms. h...

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“…PCH type 3 is associated with optic atrophy and caused by mutations in PCLO , but has only been described in one family [31]. PCH type 9 is characterized by severely delayed psychomotor development, progressive microcephaly, spasticity and seizures and caused by mutations in AMPD2 [32].…”

Section: Specific Malformations With Known Genetic Causesmentioning

confidence: 99%

The genetics of cerebellar malformations

Aldinger¹,

Doherty

2016

Seminars in Fetal and Neonatal Medicine

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SUMMARY The cerebellum has long been recognized for its role in motor co-ordination, but it is also increasingly appreciated for its role in complex cognitive behavior. Historically, the cerebellum has been overwhelmingly understudied compared to the neocortex in both humans and model organisms. However, this tide is changing as advances in neuroimaging, neuropathology, and neurogenetics have led to clinical classification and gene identification for numerous developmental disorders that impact cerebellar structure and function associated with significant overall neurodevelopmental dysfunction. Given the broad range in prognosis and associated medical and neurodevelopmental concerns accompanying cerebellar malformations, a working knowledge of these disorders and their causes is critical for obstetricians, perinatologists, and neonatologists. Here we present an update on the genetic causes for cerebellar malformations that can be recognized by neuroimaging and clinical characteristics during the prenatal and postnatal periods.

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Loss of PCLO function underlies pontocerebellar hypoplasia type III

Cited by 52 publications

References 18 publications

Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

The genetics of cerebellar malformations

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