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Fulltext Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, et al.

Am J Hum Genet, 2021 02 04;108(2):346-356.
PMID: 33513338 DOI: 10.1016/j.ajhg.2021.01.007

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Phylogenomics and the rise of the angiosperms

Zuntini AR, Carruthers T, Maurin O, Bailey PC, Leempoel K, Brewer GE, et al.

Nature, 2024 Apr 24.
PMID: 38658746 DOI: 10.1038/s41586-024-07324-0

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods1,2. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome3,4. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins5-7. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes8. This 15-fold increase in genus-level sampling relative to comparable nuclear studies9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade.
Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses

Uchiyama Y, Yamaguchi D, Iwama K, Miyatake S, Hamanaka K, Tsuchida N, et al.

Hum Mutat, 2021 01;42(1):50-65.
PMID: 33131168 DOI: 10.1002/humu.24129

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy

Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, et al.

Clin Genet, 2018 02;93(2):266-274.
PMID: 28556953 DOI: 10.1111/cge.13061

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.
Detection of copy number variations in epilepsy using exome data

Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, et al.

Clin Genet, 2018 03;93(3):577-587.
PMID: 28940419 DOI: 10.1111/cge.13144

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.
GRIN2D variants in three cases of developmental and epileptic encephalopathy

Tsuchida N, Hamada K, Shiina M, Kato M, Kobayashi Y, Tohyama J, et al.

Clin Genet, 2018 12;94(6):538-547.
PMID: 30280376 DOI: 10.1111/cge.13454

N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.
SPTAN1 encephalopathy: distinct phenotypes and genotypes

Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, et al.

J Hum Genet, 2015 Apr;60(4):167-73.
PMID: 25631096 DOI: 10.1038/jhg.2015.5

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.
Fulltext An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia

Tanaka Y, Yeoh AEJ, Moriyama T, Li CK, Kudo K, Arakawa Y, et al.

Haematologica, 2021 07 01;106(7):2026-2029.
PMID: 33504140 DOI: 10.3324/haematol.2020.266320
Fulltext PLPBP mutations cause variable phenotypes of developmental and epileptic encephalopathy

Shiraku H, Nakashima M, Takeshita S, Khoo CS, Haniffa M, Ch'ng GS, et al.

Epilepsia Open, 2018 Dec;3(4):495-502.
PMID: 30525118 DOI: 10.1002/epi4.12272

Objective: Vitamin B6-dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6-dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation.
Methods: We identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected.
Results: Each patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic-clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures.
Significance: PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures.
Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

Sakamoto M, Iwama K, Sasaki M, Ishiyama A, Komaki H, Saito T, et al.

Genet Med, 2022 Dec;24(12):2453-2463.
PMID: 36305856 DOI: 10.1016/j.gim.2022.08.007

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.
METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.
RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.
CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
Artocarpus (Moraceae)-gall midge pollination mutualism mediated by a male-flower parasitic fungus

Sakai S, Kato M, Nagamasu H

Am J Bot, 2000 Mar;87(3):440-5.
PMID: 10719005

A previously undescribed pollination system involving a monoecious tree species, Artocarpus integer (Moraceae), pollinator gall midges, and fungi is reported from a mixed dipterocarp forest in Sarawak, Borneo. The fungus Choanephora sp. (Choanephoraceae, Mucorales, Zygomycetes) infects male inflorescences of A. integer, and gall midges (Contarinia spp., Cecidomyiinae, Diptera) feed on the fungal mycelia and oviposit on the inflorescence. Their larvae also feed on the mycelia and pupate in the inflorescence. The gall midges are also attracted by female inflorescences lacking mycelia, probably due to a floral fragrance similar to that of male inflorescences. Because of the sticky pollen, dominance of Contarinia spp. in flower visitors, and pollen load observed on Contarinia spp. collected on both male and female inflorescences, Artocarpus integer is thought to be pollinated by the gall midges. Although several pathogenic fungi have been reported to have interactions with pollinators, this is the first report on a pollination mutualism in which a fungus plays an indispensable role. The pollination system described here suggests that we should be more aware of the roles fungi can play in pollinations.
Three pollination guilds and variation in floral characteristics of Bornean gingers (Zingiberaceae and Costaceae)

Sakai S, Kato M, Inoue T

Am J Bot, 1999 May;86(5):646-58.
PMID: 10330067

The pollinators of 29 ginger species representing 11 genera in relation to certain floral morphological characteristics in a mixed-dipterocarp forest in Borneo were investigated. Among the 29 species studied, eight were pollinated by spiderhunters (Nectariniidae), 11 by medium-sized Amegilla bees (Anthophoridae), and ten by small halictid bees. These pollination guilds found in gingers in Sarawak are comparable to the pollination guilds of neotropical Zingiberales, i.e., hummingbird-, and euglossine-bee-pollinated guilds. Canonical discriminant analysis revealed that there were significant correlations between floral morphology and pollination guilds and suggests the importance of plant-pollinator interactions in the evolution of floral morphology. Most species in the three guilds were separated on the plot by the first and second canonical variables. Spiderhunter-pollinated flowers had longer floral tubes, while Amegilla-pollinated flowers had wider lips than the others, which function as a platform for the pollinators. Pistils and stamens of halictid-pollinated flowers were smaller than the others. The fact that gingers with diverse morphologies in a forest with high species diversity were grouped into only three pollination guilds and that the pollinators themselves showed low species diversity suggests that many species of rare understory plants have evolved without segregating pollinators in each pollination guild.
Beetle pollination of Shorea parvifolia (section Mutica, Dipterocarpaceae) in a general flowering period in Sarawak, Malaysia

Sakai S, Momose K, Yumoto T, Kato M, Inoue T

Am J Bot, 1999 Jan;86(1):62-9.
PMID: 21680346

Pollination ecology of an emergent tree species, Shorea (section Mutica) parvifolia (Dipterocarpaceae), was studied using the canopy observation system in a lowland dipterocarp forest in Sarawak, Malaysia, during a general flowering period in 1996. Although the species has been reported to be pollinated by thrips in Peninsular Malaysia, our observations of flower visitors and pollination experiments indicated that beetles (Chrysomelidae and Curculionidae, Coleoptera) contributed to pollination of S. parvifolia in Sarawak. Beetles accounted for 74% of the flower visitors collected by net-sweeping, and 30% of the beetles carried pollen, while thrips accounted for 16% of the visitors, and 12% of the thrips carried pollen. The apical parts of the petals and pollen served as a reward for the beetles. Thrips stayed inside the flower almost continuously after arrival, and movements among flowers were rare. Fruit set was significantly increased by introduction of beetles to bagged flowers, but not by introduction of thrips. Hand-pollination experiments and comparison of fruit set in untreated, bagged, and open flowers suggested that S. parvifolia was mainly outbreeding.
Fulltext Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay

Saitsu H, Watanabe M, Akita T, Ohba C, Sugai K, Ong WP, et al.

Sci Rep, 2016 07 20;6:30072.
PMID: 27436767 DOI: 10.1038/srep30072

Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic syndromes characterized by migrating polymorphous focal seizures. Whole exome sequencing (WES) in ten sporadic and one familial case of EIMFS revealed compound heterozygous SLC12A5 (encoding the neuronal K(+)-Cl(-) co-transporter KCC2) mutations in two families: c.279 + 1G > C causing skipping of exon 3 in the transcript (p.E50_Q93del) and c.572 C >T (p.A191V) in individuals 1 and 2, and c.967T > C (p.S323P) and c.1243 A > G (p.M415V) in individual 3. Another patient (individual 4) with migrating multifocal seizures and compound heterozygous mutations [c.953G > C (p.W318S) and c.2242_2244del (p.S748del)] was identified by searching WES data from 526 patients and SLC12A5-targeted resequencing data from 141 patients with infantile epilepsy. Gramicidin-perforated patch-clamp analysis demonstrated strongly suppressed Cl(-) extrusion function of E50_Q93del and M415V mutants, with mildly impaired function of A191V and S323P mutants. Cell surface expression levels of these KCC2 mutants were similar to wildtype KCC2. Heterologous expression of two KCC2 mutants, mimicking the patient status, produced a significantly greater intracellular Cl(-) level than with wildtype KCC2, but less than without KCC2. These data clearly demonstrated that partially disrupted neuronal Cl(-) extrusion, mediated by two types of differentially impaired KCC2 mutant in an individual, causes EIMFS.
Fulltext Identifying the Common Genetic Basis of Antidepressant Response

Pain O, Hodgson K, Trubetskoy V, Ripke S, Marshe VS, Adams MJ, et al.

Biol Psychiatry Glob Open Sci, 2022 Apr;2(2):115-126.
PMID: 35712048 DOI: 10.1016/j.bpsgos.2021.07.008

BACKGROUND: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.
METHODS: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.
RESULTS: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.
CONCLUSIONS: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms

Nakashima M, Kato M, Matsukura M, Kira R, Ngu LH, Lichtenbelt KD, et al.

J Hum Genet, 2020 Sep;65(9):727-734.
PMID: 32341456 DOI: 10.1038/s10038-020-0758-2

The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.
De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy

Nakashima M, Kato M, Aoto K, Shiina M, Belal H, Mukaida S, et al.

Ann Neurol, 2018 04;83(4):794-806.
PMID: 29534297 DOI: 10.1002/ana.25208

OBJECTIVE: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.
METHODS: We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.
RESULTS: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.
INTERPRETATION: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794-806.
Resource use of insect seed predators during general flowering and seeding events in a Bornean dipterocarp rain forest

Nakagawa M, Itioka T, Momose K, Yumoto T, Komai F, Morimoto K, et al.

Bull. Entomol. Res., 2003 Oct;93(5):455-66.
PMID: 14658448

Insect seed predators of 24 dipterocarp species (including the genera ot Dipterocarpus, Dryobalanops and Shorea) and five species belonging to the Moraceae, Myrtaceae, Celastraceae and Sapotaceae were investigated. In a tropical lowland dipterocarp forest in Sarawak, Malaysia, these trees produces seeds irregularly by intensely during general flowering and seeding events in 1996 and/or 1998. Dipterocarp seeds were preyed on by 51 insect species (11 families), which were roughly classified into three taxonomic groups: smaller moths (Trotricidae, Pyralidae, Crambidae, Immidae, Sesiidae, and Cosmopterigidae), scolytids (Scolydae) and weevils (Curdulionidae, Apionidae, Anthribidae, and Attelabidae). Although the host-specificity of invertebrate seed predators has been assumed to be high in tropical forests, it was found that the diet ranges of some insect predators were relatively wide and overlapped one another. Most seed predators that were collected in both study years changes their diets between general flowering and seeding events. The results of cluster analyses based on the number of adult of each predator species that emerged from 100 seeds of each tree species, suggested that the dominant species was not consistent, alternating between the two years.
Pollination biology in a lowland dipterocarp forest inSarawak, Malaysia. I. Characteristics of the plant-pollinator communityin a lowland dipterocarp forest

Momose K, Yumoto T, Nagamitsu T, Kato M, Nagamasu H, Sakai S, et al.

Am J Bot, 1998 Oct;85(10):1477-501.
PMID: 21684899

Flowerings and flower visitors were observed continuously in alowland dipterocarp forest in Sarawak, Malaysia, for 53 mo in1992-1996. Flower visitors of 270 plant species were observed orcollected, and pollinators were assessed by observing body contact tostigmas and anthers. We recognized 12 categories of pollination systems.Among them, plants pollinated by social bees included the largest numberof species (32%) and were followed by beetle-pollinated species(20%). Pollination systems were significantly related with somefloral characters (flowering time of day, reward, and floral shape), butnot with floral color. Based on the relationships between pollinatorsand floral characters, we described pollination syndromes found in alowland dipterocarp forest. The dominance of social bees and beetlesamong pollinators is discussed in relation to the general floweringobserved in dipterocarp forests of West Malesia. In spite of high plantspecies diversity and consequent low population densities of lowlanddipterocarp forests, long-distance-specific pollinators were uncommoncompared with theNeotropics.
Fulltext Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al.

Am J Hum Genet, 2016 Oct 06;99(4):950-961.
PMID: 27666374 DOI: 10.1016/j.ajhg.2016.08.005

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

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