RESUMEN
Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.
Asunto(s)
Amenorrea/genética , Inestabilidad Cromosómica/genética , Enanismo/genética , Proteínas de Mantenimiento de Minicromosoma/genética , Polimorfismo de Nucleótido Simple/genética , Insuficiencia Ovárica Primaria/genética , Cariotipo Anormal , Adolescente , Adulto , Secuencia de Bases , Línea Celular , Consanguinidad , Roturas del ADN de Doble Cadena , Reparación del ADN , Exoma/genética , Femenino , Recombinación Homóloga , Homocigoto , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Linaje , Sitios de Empalme de ARN , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. Setting: Academic research institution. Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels. Interventions: None. Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway. Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.
Asunto(s)
Envejecimiento/genética , Daño del ADN/genética , Reparación del ADN/genética , Proteínas de Mantenimiento de Minicromosoma/genética , Insuficiencia Ovárica Primaria/genética , Adulto , Femenino , Humanos , Análisis de Secuencia de ADNRESUMEN
By switching between linear and circular polarization in the irradiation of supersaturated solutions of the amino acid glycine in water with intense nanosecond pulses of near-infrared laser light, we have obtained the gamma and alpha phases, respectively, through nonphotochemical light-induced nucleation (NPLIN). This is the first report of light polarization controlling crystal structure. The intensity dependence of NPLIN in aqueous urea is also reported.