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Indianapolis, IN, United States

Gavvovidis I.,University of Wurzburg | Pohlmann C.,Charite - Medical University of Berlin | Marchal J.A.,Charite - Medical University of Berlin | Marchal J.A.,University of Jaen | And 7 more authors.
Cell Cycle | Year: 2010

Mutations in the MCPH1 gene cause primary microcephaly associated with a unique cellular phenotype of misregulated chromosome condensation. The encoded protein contains three BRCT domains, and accumulating data show that MCPH1 is involved in the DNA damage response. However, most of this evidence has been generated by experiments using RNA interference (RNAi) and cells from non-human model organisms. Here, we demonstrate that patient-derived cell lines display a proficient G2/M checkpoint following ionizing irradiation (IR) despite homozygous truncating mutations in MCPH1. Moreover, chromosomal breakage rates and the relocation to DNA repair foci of several proteins functioning putatively in an MCPH1-dependent manner are normal in these cells. However, the MCPH1-deficient cells exhibit a slight delay in re-entering mitosis and delayed resolution of γH2AX foci following IR. Analysis of chromosome condensation behavior following IR suggests that these latter observations may be related to hypercondensation of the chromatin in cells with MCPH1 mutations. Our results indicate that the DNA damage response in human cells with truncating MCPH1 mutations differs significantly from the damage responses in cells of certain model organisms and in cells depleted of MCPH1 by RNAi. These subtle effects of human MCPH1 deficiency on the cellular DNA damage response may explain the absence of cancer predisposition in patients with biallelic MCPH1 mutations. © 2010 Landes Bioscience. Source

Escobar L.F.,Medical Genetics and Neurodevelopmental Pediatric Center | Wagner S.,Medical Genetics and Neurodevelopmental Pediatric Center | Tucker M.,Medical Genetics and Neurodevelopmental Pediatric Center | Tucker M.,Center for Prenatal Diagnosis | Wareham J.,Section of Neonatology
Journal of Perinatology | Year: 2012

A total of 11 types of glycogen storage disorders have been recognized with variable clinical presentations. Type IV, also known as Andersen disease, represents a rare subtype that can induce severe clinical findings early in life. We report on a patient with early fetal onset of symptoms with severe neuromuscular findings at birth. The pregnancy was further complicated by polyhydramnios and depressed fetal movement. At birth severe hypotonia was noticed requiring active resuscitation and then mechanical ventilation. His lack of expected course for hypoxic ischemic encephalopathy prompted genetic testing, including a muscle biopsy, which confirmed the diagnosis of glycogen storage disease IV (GSD IV). Mutation analysis of the glycogen branching enzyme 1 gene demonstrated a previously unrecognized mutation. We review recent information on early presentation of GSD IV with particular interest in the presentation of the neonatal lethal neuromuscular form of this rare disorder. © 2012 Nature America, Inc. All rights reserved. Source

Hao Y.,Center for Prenatal Diagnosis
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2011

To conduct molecular and prenatal diagnosis for a couple with β thalassemia. Blood routine examination and hemoglobin analysis were used for screening of thalassemia. Seventeen common Chinese mutations of β thalassemia were detected for the carriers with β thalassemia using PCR/RDB. The unknown mutation of β thalassemia was identified by DNA sequencing and DHPLC analysis. The husband was heterozygote of CD41/42 (-TCTT). The wife carried a mutation IVS-I-110 (G→A) of β thalassemia having not been reported in Chinese so far. The fetus was a double mutated heterozygote of IVS-I-110 (G→A) and CD41/42 (-TCTT). The pregnancy was terminated. Mutation IVS-I-110 (G→A) of β thalassemia in Chinese is of importance to the genetic counseling and prenatal diagnosis of thalassemia. Source

Foster T.L.,St. Vincent Womens Hospital | Moore E.S.,St. Vincent Womens Hospital | Sumners J.E.,St. Vincent Womens Hospital | Sumners J.E.,Center for Prenatal Diagnosis
Journal of Obstetrics and Gynaecology | Year: 2011

This retrospective cohort study identifies complications associated with transabdominal cerclage (TAC). In 300 procedures performed over a 24 year time span, 11 (3.7%) surgical complications were encountered. Fetal loss (prior to 20 weeks) occurred in 4.1% of pregnancies. The median estimated blood loss among patients was 100 ml, with blood loss sufficient to require transfusion only once. Considering patients with classical indications, the gestational age at delivery was greater (37 weeks) after TAC than in the latest pre-TAC pregnancy (24 weeks) (p < 0.001). Lower uterine dehiscence in four patients and uterine rupture in one, underscore the advisability of early term delivery after fetal lung maturity is assured. A survival rate of 98.0% was calculated among infants that were delivered at >24 weeks' gestation. Our results demonstrate that complications encountered in placing a TAC were unusual and generally manageable. This communication may assist the surgeon to balance risks in individual clinical circumstances more adequately. © 2011 Informa UK, Ltd. Source

Shang X.,Southern Medical University | Li Q.,Southern Medical University | Cai R.,Center for Prenatal Diagnosis | Huang J.,Southern Medical University | And 2 more authors.
Clinical Genetics | Year: 2013

The HKαα allele is a rearrangement occurring in the α-globin gene cluster containing both the -α3.7 and αααanti4.2 unequal crossover junctions. The anti-HKαα allele is the reciprocal product containing both the -α4.2 and αααanti3.7 unequal crossover junctions, which had been predicted but had not been detected previously. The phenotypic feature and population frequency of these two unusual alleles were not described. We report the identification of nine individuals carrying the HKαα allele and two individuals carrying the anti-HKαα allele in southern China and describe their phenotype and haplotype data. The molecular structures of HKαα allele and anti-HKαα allele were confirmed by two-round nested polymerase chain reaction assay. The mechanism of origin of both alleles is related to probably simultaneous double crossover. Heterozygotes of HKαα or anti-HKαα allele show a normal hematological phenotype. Finally, we report the carrier rates of these both alleles in the Guangxi Zhuang Autonomous Region of southern China, namely, ~0.07% for the HKαα allele and ~0.02% for the anti-HKαα allele. © 2012 John Wiley & Sons A/S. Source

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