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Heterozygous - Europe PMC

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Last Updated: 11 September 2022

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High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER + breast cancer.

For the treatment of advanced estrogen receptor-positive breast cancer, CDK4/6 inhibitors as well as endocrine therapy have shown improved antitumor activity than endocrine therapy alone. Here, we show that p16 overexpression is associated with reduced antitumor activity in patient-derived xenografts and estrogen receptor-positive breast cancer cell lines, as well as the reduced sensitivity of early and advanced breast cancer patients to CDK4/6 inhibitors.

Source link: https://europepmc.org/article/MED/36071033


Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy.

Developmental dysplasia of the hip is one of the most common congenital skeletal malformations; however, its etiology is uncertain. Here, we performed whole-exome sequencing in eight DDH families, as well as targeted sequencing of 68 sporadic DDH patients. In two families and seven unrelated patients, we discovered likely pathogenic variants in the LRP1 gene. All patients with the LRP1 geneotype had a typical DDH phenotype. The heterozygous Lrp1 knockout mouse demonstrated phenotypes recapitulating the human DDH phenotypes, indicating that Lrp1 loss of function leads to DDH. A missense variant of the Lrp1 knockin mice with a missing DDH phenotype were both milder in heterozygotes and greater in homozygotes than those of the Lrp1 KO mouse, which was milder in heterozygotes and higher in homozygotes. Lrp1 deficiency caused decreased autophagy levels after significant u03b2-catenin up-regulation and suppression of chondrocyte marker genes during mice bone marrow stem cells and ATDC5 in the early stages of chondrogenic induction of mouse bone marrow stem cells and ATDC5.

Source link: https://europepmc.org/article/MED/36067312


Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.

Most patients with congenital abnormalities of the kidney and urinary tract remain undiagnosed. We used whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain abnormalities, revealing a rare heterozygous missense variant of the DACT1 gene encoding a cytoplasmic WNT signaling mediator. Our patient's features closely matchtownes-Brocks syndrome 2 previously described in a family with a DACT1 nonsense variant as well as those of Dact1-deficient mice. We therefore investigated the role of DACT1 in CAKUT pathogenesis. Mutant DACT1 binds to DVL2 for a variety of gastrointestinal disorders, most likely pathogenic and mainly maternally inherited, were discovered in the interaction zone with DVL2, and biochemical studies revealed reduced binding of mutant DACT1 to DVL2. Dact1 was expressed in organs affected by the DACT1 variants' morphology, anal canal, vertebrae, and brain during murine development, and the kidney, anal canal, vertebrae, and brain.

Source link: https://europepmc.org/article/MED/36066768


Paediatric patients with heterozygous familial hypercholesterolaemia treated with evolocumab for 80 weeks (HAUSER-OLE): a single-arm, multicentre, open-label extension of HAUSER-RCT.

Compared to placebo, the HAUSER-RCT study found that 24 weeks of evolocumab in paediatric patients with heterozygous familial hypercholesterolaemia was safe and raised lipid values. Patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no significant health-emergent adverse events were eligible to enroll in HAUSER-OLE. For 80 more weeks, the patients were given open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 weeks. Changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE demonstrated Efficacy. The mean percentage change in LDL cholesterol from baseline was -35 percent at week 80, with a score of -35 percent. After 80 weeks of therapy, evolocumab was safe, well tolerated, and contributed to sustained declines in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia.

Source link: https://europepmc.org/article/MED/36075246


A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers.

In his two heterozygous young children, Aim To describe a family's segregation of a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. In DNA from the index case, an exome sequencing was performed, resulting in the discovery of the ZNF469 gene causal variant in his relatives by subsequent Sanger sequencing. The c. 2340delC gene variant in DNA from both siblings was found heterozygosity by Sanger sequencing. Conclusions Our findings extend the genetic spectrum associated with brittle cornea syndrome and include the first evidence of early corneal abnormalities in people with monoallelic ZNF469 variants.

Source link: https://europepmc.org/article/MED/36048286


Fetal Presentation of Walker-Warburg Syndrome with Compound Heterozygous POMT2 Missense Mutations.

Background: Walker-Warburg syndrome is a congenital muscular dystrophy, hydrocephalus, cobblestone lissencephaly, and retinal dysplasia. Case study: We present a case study: At ultrasound clear triventricular hydrocephalus in a fetus with WWS. Two heterozygous mutations in the POMT2 gene were found in the next generation sequencing of 193 genes, performed on fetal DNA isolated from amniocytes. Conclusion: Compound heterozygous mutations in the POMT2 gene resulted in a severe cerebral fetal phenotype that was detected prenatally at midgestations that allow therapeutic pregnancy terminations.

Source link: https://europepmc.org/article/MED/36048137


Generation of human induced pluripotential stem cells from individuals with complex heterozygous, isogenic corrected, and homozygous Bloc1s1 mutations.

Additional people with leukodystrophy with either intricate heterozygous or homozygous point mutations were found in the Vanderver laboratory. Cell lines from these patients' parents of the complex heterozygous mutations patient and the CRISPR isogenic corrected iPSC-line were induced.

Source link: https://europepmc.org/article/MED/36070637

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions