The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

We sequenced more than 52,500 single cells from embryonic day 11.5 (E11.5) postembryonic day 5 (P5) gonads and performed lineage tracing to analyze primordial follicles and wave 1 medullar follicles during mouse fetal and perinatal oogenesis. Germ cells clustered into six meiotic substages, as well as dying/nurse cells. Wnt-expressing bipotential precursors already present at E11.5 are followed at each developmental stage by two groups of ovarian pregranulosa (PG) cells. One PG group, bipotential pregranulosa (BPG) cells, derives directly from bipotential precursors, expresses Foxl2 early, and associates with cysts throughout the ovary by E12.5. A second PG group, epithelial pregranulosa (EPG) cells, arises in the ovarian surface epithelium, ingresses cortically by E12.5 or earlier, expresses Lgr5, but delays robust Foxl2 expression until after birth. By E19.5, EPG cells predominate in the cortex and differentiate into granulosa cells of quiescent primordial follicles. In contrast, medullar BPG cells differentiate along a distinct pathway to become wave 1 granulosa cells. Reflecting their separate somatic cellular lineages, second wave follicles were ablated by diptheria toxin treatment of Lgr5-DTR-EGFP mice at E16.5 while first wave follicles developed normally and supported fertility. These studies provide insights into ovarian somatic cells and a resource to study the development, physiology, and evolutionary conservation of mammalian ovarian follicles.

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“…4 B ). These included the ketogenic gene Hmgcs2 ( 70 ), the hydroxysteroid dehydrogenase gene Ark1c14 ( 71 ), and multiple others ( Fig. 4 B ).…”

Section: Resultsmentioning

confidence: 99%

Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary

Niu

Spradling

2020

Proc. Natl. Acad. Sci. U.S.A.

170

205

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“…5 a, Agt (angiotensinogen) was expressed in ALCs but not in Sertoli or germ cells in adult testes. Enriched expression in ALCs has previously been observed for Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthase 2) 35 , 36 , Lcn2 (lipocalin-2) 37 , and Sepp1 (selenoprotein P, plasma, 1) 38 . A high level of Ptgds (prostaglandin D2 synthase) expression was detected in ALCs, although the expression was also detected in Sertoli cells from some, but not all, testicular tubules 39 .…”

Section: Resultsmentioning

confidence: 65%

Gene expression and functional abnormalities in XX/Sry Leydig cells

Yanai

Baba

Inui

et al. 2021

Sci Rep

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The SRY gene induces testis development even in XX individuals. However, XX/Sry testes fail to produce mature sperm, due to the absence of Y chromosome carrying genes essential for spermatogenesis. XX/Sry Sertoli cells show abnormalities in the production of lactate and cholesterol required for germ cell development. Leydig cells are essential for male functions through testosterone production. However, whether XX/Sry adult Leydig cells (XX/Sry ALCs) function normally remains unclear. In this study, the transcriptomes from XY and XX/Sry ALCs demonstrated that immediate early and cholesterogenic gene expressions differed between these cells. Interestingly, cholesterogenic genes were upregulated in XX/Sry ALCs, although downregulated in XX/Sry Sertoli cells. Among the steroidogenic enzymes, CYP17A1 mediates steroid 17α-hydroxylation and 17,20-lyase reaction, necessary for testosterone production. In XX/Sry ALCs, the latter reaction was selectively decreased. The defects in XX/Sry ALCs, together with those in the germ and Sertoli cells, might explain the infertility of XX/Sry testes.

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“…We detected the missense mutation c.1502G > A/p.R501Q in Patient 6 in the compound heterozygous state, and a previous study has reported a Chinese case in the homozygous state (Ma and Yu, 2018). Previous reports have also suggested that arginine at position 501 is critical to enzymatic function (Bagheri-Fam et al, 2020). Moreover, variation in amino acids in the same position, c.1502G > C/p.R501P, has also been found in two Thai patients (Rojnueangnit et al, 2020).…”

Section: Discussionmentioning

confidence: 96%

Clinical, Biochemical, Molecular, and Outcome Features of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency in 10 Chinese Patients

Shen

Chen

et al. 2022

Front. Genet.

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Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare autosomal recessive metabolic disorder caused by mutations of the HMGCS2 gene. To date, no more than 60 patients have been reported throughout the world.Purpose: To analyze the clinical, biochemical, molecular, and outcome features of HMGCS2D in a case series of 10 new Chinese patients.Methods: This retrospective study includes 10 Chinese patients diagnosed with HMGCS2D. We collected and analyzed clinical data for all patients. We also reviewed clinical data for 39 cases that had been reported previously.Results: All of our patients had experienced their first metabolic crisis before 12 months old. The most common clinical manifestations were anorexia, dyspnea, and disturbance of consciousness (10/10), followed by vomiting (8/10), fever (7/10), cough (4/10), diarrhea, and seizures (3/10). Each patient (10/10) had a different degree of hepatomegaly and increased aminotransferase, severe metabolic acidosis, and hypofibrinogenemia. 9 patients presented with severe hypoglycemia and weak positives on qualitative tests of urinary ketone body. Patient 3 was the only one without hypoglycemia. Five patients had hypocalcemia, five patients had hyperammonemia, four patients had hyperuricemia, and three had hypertriglyceridemia. During the metabolic acidosis episode, we observed high dicarboxylic acid values in urine, and the elevated ratio of blood acetylcarnitine to free carnitine may have been an additional biochemical signature. However, all returned to normal during the interictal interval. Molecular analysis identified 15 variants in the HMGCS2 gene, of which 10 were novel (c.220G>A/p.E74K, c.407A>G/p.D136G, c.422T>A/p.V141D, c.719A>C/p.D240A, c.821G>A/p.R274H, c.39dupA/p.L14Tfs*59, c.1394delA/p.N465Tfs*10, c.788delT/p.L263Cfs*36, c.717T>G/p.Y239*, and c.1017-2A>G). Combining these with previous cases, the known mutation c.1201G>T/p.E401* has been found in 6/40 (15.0%) of mutated alleles in 21 Chinese patients from 20 families, while none have been found in other populations. We found that patients with biallelic truncation mutation appeared to show a more severe clinical condition through a literature review.Conclusion: This study analyzed the phenotypic and genetic features of HMGCS2D in a Chinese case series. We also expanded the HMGCS2 mutational spectrum with 10 novel variants. The c.1201G>T/p.E401* mutation was the most frequent, representing 15.0% of the mutated alleles in reported unrelated Chinese patients, and thus, it may be a hot spot mutation.

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The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

Cited by 13 publications

References 67 publications

Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary

Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary

Gene expression and functional abnormalities in XX/Sry Leydig cells

Clinical, Biochemical, Molecular, and Outcome Features of Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency in 10 Chinese Patients

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