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Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492


Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
Dev Cell ; 51(6): 713-729.e6, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31735666


The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.

Divisão Celular Assimétrica/fisiologia , Polaridade Celular/fisiologia , Proteínas de Membrana/genética , Microcefalia/virologia , Neurônios/metabolismo , Proteínas Nucleares/genética , Animais , Divisão Celular , Drosophila melanogaster/metabolismo , Humanos , Mutação , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Neurônios/citologia , Zika virus
J Clin Endocrinol Metab ; 104(8): 3049-3067, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042289


CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

Insuficiência Ovariana Primária/genética , Sequenciamento Completo do Exoma , Proteínas de Ciclo Celular/genética , Estudos de Coortes , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Frequência do Gene , Humanos , Hipogonadismo/genética , Imunoglobulinas/genética , Proteínas de Manutenção de Minicromossomo/genética , Insuficiência Ovariana Primária/etiologia
J Clin Orthop Trauma ; 10(2): 296-301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828197


A prospective, comparative study was done over a period of 3 years to compare the complications and functional results of two treatment modalities of unstable intertrochanteric fractures of the femur in the elderly; i.e closed reduction and internal fixation (CRIF) with proximal femur nail (PFN) and primary cemented hemireplacement arthroplasty (HRA) with bipolar prosthesis. 100 elderly patients with unstable intertrochanteric fractures of femur were studied over a period of 3 years. 50 patients underwent CRIF with PFN and 50 patients were treated with primary cemented hemireplacement arthroplasty with bipolar prosthesis. Harris Hip score analysis revealed that the difference between the patients treated with cemented hemiarthroplasty and proximal femoral nailing was statistically significant in favour of the hemiarthroplasty group within the first 3 months. However, this difference diminished at the 6th month time point and reversed at the 12 month time point indicating a better functional outcome of Proximal Femur Nail in the long term. Although cemented hemireplacement arthhroplasty allows early pain free mobilization and has a good short term outcome, over time it is associated with a variety of complications which significantly affects quality of life of patients. On the other hand, although patients treated with PFN had delayed post op mobilization, they had better results when followed up at 1 year post surgery.