While sperm mosaicism has few consequences for men, the offspring and future generations are unwitting recipients of gonadal cell mutations, often yielding severe disease. Recent studies, fueled by ...emergent technologies, show that sperm mosaicism is a common source of de novo mutations (DNMs) that underlie severe pediatric disease as well as human genetic diversity. Sperm mosaicism can be divided into three types: Type I arises during sperm meiosis and is non-age dependent; Type II arises in spermatogonia and increases as men age; and Type III arises during paternal embryogenesis, spreads throughout the body, and contributes stably to sperm throughout life. Where Types I and II confer little risk of recurrence, Type III may confer identifiable risk to future offspring. These mutations are likely to be the single largest contributor to human genetic diversity. New sequencing approaches may leverage this framework to evaluate and reduce disease risk for future generations.
Sperm is the only cell type transmitting male genetic information to offspring, with each cell containing dozens of mutations unique to this cell or shared with only a subset of others.The three types of sperm mosaicism are distinguished based on their cell and time of origin and their potential of familial or population recurrence.Genome-wide risk assessment of individual mutations in sperm can characterize the transmission risk for individuals to their offspring.Sperm mosaicism contributes to human genetic diversity derived from de novo mutation and increases as the population expands and paternal age increases.
Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India ...revealed a
KIAA0556
homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum.
Mutations in the
doublecortin (DCX) gene in human or targeted disruption of the
cdk5 gene in mouse lead to similar cortical lamination defects in the developing brain. Here we show that Dcx is ...phosphorylated by Cdk5. Dcx phosphorylation is developmentally regulated and corresponds to the timing of expression of p35, the major activating subunit for Cdk5. Mass spectrometry and Western blot analysis indicate phosphorylation at Dcx residue Ser297. Phosphorylation of Dcx lowers its affinity to microtubules in vitro, reduces its effect on polymerization, and displaces it from microtubules in cultured neurons. Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. These results suggest that Dcx phosphorylation by Cdk5 regulates its actions on migration through an effect on microtubules.
Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and ...progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (
ASNS
, EC 6.3.5.4), particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the
ASNS
gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the
ASNS
gene to four. This finding extends the
ASNS
pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.
Joubert syndrome (JS) is a developmental brain disorder characterized by cerebellar vermis hypoplasia, abnormal eye movement, ataxia and mental retardation. Mutations in CEP290 mutations are ...responsible for the cerebello–oculo–renal subtype of JS that includes kidney cysts and retinal degeneration, two phenotypes commonly linked to ciliopathies. CEP290 mutations are also associated with Meckel–Gruber syndrome and Bardet–Biedl syndrome (BBS). Here we demonstrate that CEP290 interacts with a centriolar satellite protein PCM-1, which is implicated in BBS4 function. CEP290 binds to PCM-1 and localizes to centriolar satellites in a PCM-1- and microtubule-dependent manner. The depletion of CEP290 disrupts subcellular distribution and protein complex formation of PCM-1. In accord with PCM-1’s role in microtubule organization, CEP290 knockdown causes the disorganization of the cytoplasmic microtubule network. Moreover, we show that both CEP290 and PCM-1 are required for ciliogenesis and are involved in the ciliary targeting of Rab8, a small GTPase shown to collaborate with BBS protein complex to promote ciliogenesis. Our results suggest that PCM-1 is a potential mediator that may link CEP290 with BBS proteins in common molecular pathways.
After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic ...helix-loop-helix (bHLH) transcription factors not only initiate neuronal differentiation but also potentiate cell migration. Mechanistically, proneural bHLH factors regulate the expression of genes critically involved in migration, including down-regulation of RhoA small GTPase and up-regulation of doublecortin and p35, which, in turn, modulate the actin and microtubule cytoskeleton assembly and enable newly generated neurons to migrate. In addition, we report that several DNA-binding-deficient proneural genes that fail to initiate neuronal differentiation still activate migration, whereas a different mutation of a proneural gene that causes a failure in initiating cell migration still leads to robust neuronal differentiation. Collectively, these data suggest that transcription programs for neurogenesis and migration are regulated by bHLH factors through partially distinct mechanisms.
Early life experience shapes neural genome Song, Saera; Gleeson, Joseph G
Science (American Association for the Advancement of Science),
03/2018, Letnik:
359, Številka:
6382
Journal Article
Recenzirano
Transposons accumulate in neurons of pups with lack of maternal care in mice
The brain is constantly changing in response to environmental experiences throughout life. Mounting evidence from animal ...and human studies suggests that brain development and behavior are influenced by early life experiences. Several compelling experimental models have been developed to study the effect of early life experiences on the brain, such as stress, exposure to toxins, availability of nutrients, adversity, and quality of maternal care (
1
). The relationship between genes and environment on the brain and how they affect behavior has been a long-standing issue. Can the genome of individual brain cells be changed by environmental factors? If so, which types of genetic changes can result? What is the molecular basis of this genetic diversity? What are the physiological implications? On page 1395 of this issue, Bedrosian
et al.
(
2
) explore one possibility for how neuronal genomes can exhibit plasticity in response to environmental factors during early life, providing integrative evidence for the effect of early maternal care on the genomes of neurons.
Abstract Aim Molybdenum cofactor deficiency (MoCD) and Sulfite oxidase deficiency (SOD) are rare autosomal recessive conditions of sulfur-containing amino acid metabolism with overlapping clinical ...features and emerging therapies. The clinical phenotype is indistinguishable and they can only be differentiated biochemically. MOCS1, MOCS2, MOCS3, and GPRN genes contribute to the synthesis of molybdenum cofactor, and SUOX gene encodes sulfite oxidase. The aim of this study was to elucidate the clinical, radiological, biochemical and molecular findings in patients with SOD and MoCD. Methods Detailed clinical and radiological assessment of 9 cases referred for neonatal encephalopathy with hypotonia, microcephaly, and epilepsy led to a consideration of disorders of sulfur-containing amino acid metabolism. The diagnosis of six with MoCD and three with SOD was confirmed by biochemical tests, targeted sequencing, and whole exome sequencing where suspicion of disease was lower. Results Novel SUOX mutations were detected in 3 SOD cases and a novel MOCS2 mutation in 1 MoCD case. Most patients presented in the first 3 months of life with intractable tonic-clonic seizures, axial hypotonia, limb hypertonia, exaggerated startle response, feeding difficulties, and progressive cystic encephalomalacia on brain imaging. A single patient with MoCD had hypertrophic cardiomyopathy, hitherto unreported with these diseases. Interpretation Our results emphasize that intractable neonatal seizures, spasticity, and feeding difficulties can be important early signs for these disorders. Progressive microcephaly, intellectual disability and specific brain imaging findings in the first year were additional diagnostic aids. These clinical cues can be used to minimize delays in diagnosis, especially since promising treatments are emerging for MoCD type A.
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