Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure.

BACKGROUND: Primary gonadal failure is characterised by primary amenorrhoea or early menopause in females, and oligospermia or azoospermia in males. Variants of the minichromosome maintenance complex component 8 gene (MCM8) have recently been shown to be significantly associated with women's menopausal age in genome-wide association studies. Furthermore, MCM8-knockout mice are sterile. The objective of this study was to elucidate the genetic aetiology of gonadal failure in two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male. METHODS AND RESULTS: Using whole exome sequencing, we identified two novel homozygous mutations in the MCM8 gene: a splice (c.1954-1G>A) and a frameshift (c.1469-1470insTA). In each consanguineous family the mutation segregated with the disease and both mutations were absent in 100 ethnically matched controls. The splice mutation led to lack of the wild-type transcript and three different aberrant transcripts predicted to result in either truncated or significantly shorter proteins. Quantitative analysis of the aberrantly spliced transcripts showed a significant decrease in total MCM8 message in affected homozygotes for the mutation, and an intermediate decrease in heterozygous family members. Chromosomal breakage following exposure to mitomcyin C was significantly increased in cells from homozygous individuals for c.1954-1G>A, as well as c.1469-1470insTA. CONCLUSIONS: MCM8, a component of the pre-replication complex, is crucial for gonadal development and maintenance in humans-both males and females. These findings provide new insights into the genetic disorders of infertility and premature menopause in women.

Bardet-Biedl syndrome in a 19-year-old male: the first case report from Palestine.

Bardet-Biedl syndrome (BBS) is a rare genetic disorder characterized by retinitis pigmentosa, polydactyly, type 2 diabetes mellitus, and obesity. This case report presents a 19-year-old male from Palestine with BBS, exhibiting delayed diagnosis and variable phenotypic expression. The patient had familial BBS history and presented with obesity, type 2 diabetes mellitus, retinitis pigmentosa, and cryptorchidism. Genetic analysis identified heterozygous missense variants in the FBN3 gene, yet additional genetic factors may contribute to the phenotype. Renal abnormalities included kidney shrinkage and mild hydronephrosis. Management of this patient involves a multidisciplinary approach with lifestyle modifications, surgical interventions, and supportive care. Early diagnosis, genetic counseling, and regular follow-up are crucial for improving outcomes in BBS. This report highlights diagnostic and therapeutic challenges and underscores the need for further research on this complex disorder.

Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families.

Introduction: Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycemia secondary to insulin resistance or deficiency. It is considered a major health problem worldwide. T1DM is a result of a combination of genetics, epigenetics, and environmental factors. Several genes have been associated with T1DM, including HLA, INS, CTLA4, and PTPN22. However, none of these findings have been based on linkage analysis because it is rare to find families with several diabetic individuals. Two Palestinian families with several afflicted members with variations in the mode of inheritance were identified and selected for this study. This study aimed to identify the putative causative gene(s) responsible for T1DM development in these families to improve our understanding of the molecular genetics of the disease. Methods: One afflicted member from each family was selected for Whole-Exome Sequencing. Data were mapped to the reference of the human genome, and the resulting VCF file data were filtered. The variants with the highest phenotype correlation score were checked by Sanger sequencing for all family members. The confirmed variants were analyzed in silico by bioinformatics tools. Results: In one family, the IGF1R p.V579F variant, which follows autosomal dominant inheritance, was confirmed and segregated in the family. In another family, the NEUROD1 p.P197H variant, which follows autosomal recessive inheritance, was positively confirmed and segregated. Conclusion: IGF1R p.V579F and NEUROD1 p.P197H variants were associated with T1DM development in the two inflicted families. Further analysis and functional assays will be performed, including the generation of mutant model cell systems, to unravel their specific molecular mechanism in the disease development.

Growth of the Kalahari Desert's bushman--the Ju/'hoansi San.

AIM: The Ju/'hoansi San (JHS) of the Kalahari Desert are the archetype of a hunter-gatherer society that practices natural fertility, living on a rich diet in a harsh environs. METHODS: To explore the evolutionary adaptation of child growth under such conditions, the present study takes a life history approach and compares the growth data of 140 JHS females and 126 JHS males age 1-25 to those in 3rd percentile American and Swedish references. The data are based on observations of the JHS that were made in 1967-1969. RESULTS: During infancy, the JHS boys lose 1.5 SDS and girls - 0.3 SDS in terms of Swedish reference. The height SDS of the JHS did not change significantly during their childhood, but growth deceleration during the juvenile period (middle childhood) was substantially greater and longer, amounting to a loss of 1.6 SDS for both girls and boys. Adolescent spurt was substantially later and smaller than that of the short-statured Americans. CONCLUSIONS: The results suggest that the short stature of the JHS is mostly established during juvenility, in adaptation to their unique living conditions.