Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have ...recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C p.Leu89Pro) and nonsense (c.585del p.Thr196Profs∗17) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.
Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated ...that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS.
Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size ...at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.
Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in ...phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.
Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in ...association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.
Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, ...which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.
Samia Temtamy Aglan, Mona; Zaki, Maha
American journal of medical genetics. Part A,
December 2021, 2021-12-00, 20211201, Volume:
185, Issue:
12
Journal Article
The study of the impact of some inherited defects in glycosylation on the biosynthesis of some lysosomal glycoproteins. Results description: Whole-exome sequencing revealed a homozygous variant; 428G ...> A; p. (R143K) in SRD5A3 in one patient and a heterozygous one c.46G > A p. (Gly16Arg) in SLC35A2 in the other patient. Both variants were predicted to be likely pathogenic. Lysosome-associated membrane glycoprotein 2 (LAMP2) immunodetection in both cases showed a truncated form of the protein. Cystinosin (CTN) protein appeared as normal and truncated forms in both patients in ratios of the mature to truncated forms of CTN were lower than the control. The levels of the truncated forms of both cellular proteins were higher in the SRD5A3-CDG case compared to the SLC35A2-CDG case. The tetrameric form of cathepsin C (CTSC) was expressed at low levels in both cases with congenital disorder of glycosylation (CDG). SLC35A2-CDG patient had one extra-unknown band while SRD5A3-CDG patient had a missing band of CTSC forms. The expression patterns of lysosomal glycoproteins could be different between different types of CDG.
Background Rett syndrome (RTT) is a rare, life-threatening, genetic neurodevelopmental disorder. Treatment in RTT encounters many challenges. Trofinetide, a modified amino-terminal tripeptide of ...insulin-like growth factor 1, has demonstrated clinically promising results in RTT. In this study, trofinetide efficacy and safety in RTT are systematically reviewed and meta-analyzed. Methods A systematic search of five electronic databases was conducted until January 2024. Review Manager 5.4 software was used for the analysis. The analysis was based on a weighted mean difference and standard error with a confidence interval (CI) of 95%, and a statistically significant P-value was considered if it was < 0.05. The study was registered on PROSPERO with registration number CRD42024499849. Quality of evidence was assessed using GRADE. Results Three randomized controlled trials (RCTs) with 276 patients were included in the analysis. Trofinetide improved both caregiver outcomes and clinical scales by improving the Rett Syndrome Behavior Questionnaire (RSBQ) (mean difference (MD): - 3.46 points, 95% CI: - 5.63 to - 1.27, P = 0.0002) and Clinical Global Impression Scale-Improvement (CGI-I) (MD: - 0.35, 95% CI: - 0.51 to - 0.18, P < 0.0001), respectively. However, trofinetide neither improved the Caregiver Top 3 Concerns Visual Analog Scale nor the Rett Motor Behavioral Assessment. Regarding safety, trofinetide was significantly associated with vomiting compared to placebo (odds ratio (OR): 3.17, 95% CI: 1.57 to 6.43, P = 0.001). After solving heterogeneity, results showed a statistically significant incidence of diarrhea in the trofinetide (200 mg) group compared to placebo (OR: 18.51, 95% CI: 9.30 to 36.84, P less than or equal to 0.00001). Conclusions Trofinetide demonstrated statistically significant improvements in CGI-I and RSBQ in pediatrics and adult patients with Rett. Side effects are limited to vomiting and diarrhea. Although diarrhea yielded an insignificant result in our analysis, it emerged as a cause for treatment discontinuation in the participating trials, and a statistically significant risk for diarrhea emerged when excluding the study using a lower dose of the drug, hence causing heterogeneity, in the meta-analysis. Given the diverse genetic landscape of RTT, future RCTs investigating correlations between RTT genotype and phenotypic improvements by trofinetide will be beneficial. RCTs encompassing male patients with larger and longer cohorts are recommended. Graphical Keywords: Rett syndrome, RTT, Trofinetide, Neurodevelopmental disorders, Systematic review, Meta-analysis
Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that ...correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.
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