Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth ...retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented
PHEX
mutations. Growth was compared in those who started treatment before (G1;
N
= 10; six boys) and after (G2;
N
= 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 interquartile range (IR) −1.3 to 0.4) and significantly (
p
= 0.004) lower in G2 (IR −2.1 (−2.8 to −1.4). Treatment duration was similar G1 8.5 (4.0–15.2) vs G2 11.9 (6.2–14.3) years;
p
= 0.56, as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (
p
= 0.009) better in G1 −0.7 (−1.5 to 0.3) vs G2 −2.0 (−2.3 to −1.0). No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.
A neurodevelopmental syndrome was recently reported in four patients with
heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate ...clinical and genetic knowledge of this syndrome.
We newly identified 17 patients with
variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes.
All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the
related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.
These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to
haploinsufficiency in neurogenesis and multiple other developmental processes.
The precise regulation of DNA replication is vital for cellular division and genomic integrity. Central to this process is the replication factor C (RFC) complex, encompassing five subunits, which ...loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. While RFC1’s role in cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is known, the contributions of RFC2–5 subunits on human Mendelian disorders is largely unexplored. Our research links bi-allelic variants in RFC4, encoding a core RFC complex subunit, to an undiagnosed disorder characterized by incoordination and muscle weakness, hearing impairment, and decreased body weight. We discovered across nine affected individuals rare, conserved, predicted pathogenic variants in RFC4, all likely to disrupt the C-terminal domain indispensable for RFC complex formation. Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression. Our integrated approach of combining in silico, structural, cellular, and functional analyses establishes compelling evidence that bi-allelic loss-of-function RFC4 variants contribute to the pathogenesis of this multisystemic disorder. These insights broaden our understanding of the RFC complex and its role in human health and disease.
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Morimoto et al. demonstrate that a multisystemic disorder is associated with the deficiency of RFC4, encoding a subunit of the replication factor C (RFC) complex required for DNA replication. Bi-allelic loss-of-function RFC4 variants lead to decreased RFC4 protein, reduced RFC subunit stability, impaired RFC complex formation, and likely impaired S phase progression.
The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often ...exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.
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•CELF2 variants disrupt nucleocytoplasmic localization and human cortical development•Nuclear translocation of CELF2 marks neural stem cells that undergo differentiation•Cytoplasmic CELF2 regulates mRNA encoding cell fate and disease-related factors•Cytoplasmic CELF2 regulates fate decisions of neural stem cells
MacPherson et al. show that the translocation of an RNA-binding protein CELF2 between the cytoplasm and the nucleus coordinates fate decisions of neural stem cells by controlling the expression of cell-fate-determination genes at the translational level. CELF2 variants that change nucleocytoplasmic localization cause abnormal brain development in humans.
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