Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing

Glazova, Olga; Bastrich, Asya; Deviatkin, Andrei A.; Onyanov, Nikita; Kaziakhmedova, S. A.; Shevkova, Liudmila; Sakr, Nawar; Petrova, Daria; Воронцова, М. А.; Volchkov, Pavel

doi:10.3390/ijms24065365

Cited by 3 publications

(3 citation statements)

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“…The mouse strain was generated by disrupting the StAR gene by deleting a part of exon 2 and all of exon 3. Corticosteroids and 0.9% sodium chloride were supplied to rescue the knockout mice during their lifetime [11,26]. A more recent model for CAH includes the Cyp11b1 null mouse, which was generated by exchanging exons 3-7 of Cyp11b1 with the cDNA encoding for the cyan fluorescent protein.…”

Section: Discussionmentioning

confidence: 99%

“…Over the last few years, there has been substantial improvement in the development of new drugs and therapies for CAH. Concomitantly, the testing of new therapies poses a challenge as the existing models have limited efficacy and are quite restrictive in scope for the disorder [11].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, to study human mutations and further delineate CAH, we developed the humanized mouse model. In our previous work, we have shown that the humanized C57BL/6NCrl-Cyp21a1 tg(CYP21A2)koe mice showed no differences in fertility, viability, and growth and, therefore, have the potential to be an excellent model to introduce mutations relevant to CAH [11,15].…”

Section: Introductionmentioning

confidence: 99%

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A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia–CYP21A2-R484Q Mutant Mouse

Thirumalasetty,

Schubert,

Naumann

et al. 2024

IJMS

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Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia–CYP21A2-R484Q Mutant Mouse

Thirumalasetty,

Schubert,

Naumann

et al. 2024

IJMS

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Congenital Adrenal Hyperplasia

Fraga,

Minaeian,

Kim

2024

Pediatrics in Review

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We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In this comprehensive review of CAH, we describe presentations at different life stages depending on disease severity. CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands. Diagnosis of CAH is most common during infancy with elevated 17-hydroxyprogesterone levels on the newborn screen in the United States. However, CAH can also present in childhood, with late-onset symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses. The growing child with CAH is treated with hydrocortisone for glucocorticoid replacement, along with increased stress doses for acute illness, trauma, and procedures. Mineralocorticoid and salt replacement may also be necessary. Although 21-hydroxylase deficiency is the most common type of CAH, there are other rare types, such as 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiency. In addition, classic CAH is associated with long-term comorbidities, including cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects. Overall, early identification and treatment of CAH is important for the pediatric patient.

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Hiperplasia suprarrenal congénita con crisis salina en un recién nacido

Vásquez Triminio,

Antúnez Williams,

Hernández Portillo

2024

BJM

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Introducción: La esteroidogénesis suprarrenal es un proceso complejo y secuencial que involucra a una serie de enzimas que actúan sobre el colesterol y determinan la síntesis mineralocorticoides, glucocorticoides, andrógenos y estrógenos. La hiperplasia suprarrenal congénita se presenta en 1:9500 a 1:20000 nacidos vivos como un trastorno autosómico recesivo que conlleva a mutación en los genes que codifican las enzimas para el proceso de la biosíntesis de esteroides suprarrenales; en mayor frecuencia ocurre por deficiencia de la enzima 21-alfa hidroxilasa. Las intervenciones incluyen el cribado neonatal temprano para evitar crisis de pérdida de sal y muerte neonatal; terapia de reemplazo hormonal; apoyo psicológico y opciones de cirugía en casos específicos para asignación de sexo. Caso clínico: Neonato de 5 días, hipoactivo, sin antecedentes familiares de enfermedad genética. Signos vitales dentro de parámetros normales para la edad, examen físico de genitales externos correspondiente a Prader 4, presencia de falo, labios mayores escrotalizados e hiperpigmentados, no se palpan gónadas. Ultrasonografía reporta ambas glándulas suprarrenales aumentadas de tamaño, se visualiza útero, ambos ovarios con imagen quística, no se observan testículos. Perfil hormonal: elevación de 17-alfa hidroxiprogesterona, adrenocorticótropa, testosterona y disminución de cortisol. Química sanguínea: creatinina normal, nitrógeno ureico elevado. Electrolitos: hiponatremia e hiperpotasemia. Se trata con dosis de estrés de esteroides por crisis salina con buena respuesta. Conclusiones: La hiperplasia suprarrenal congénita es un trastorno poco frecuente, pero susceptible de detección y tratamiento neonatal temprano con terapia de reemplazo hormonal, específicamente esteroides, que ha demostrado disminuir el riesgo de complicaciones graves.

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Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing

Cited by 3 publications

References 73 publications

A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia–CYP21A2-R484Q Mutant Mouse

A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia–CYP21A2-R484Q Mutant Mouse

Congenital Adrenal Hyperplasia

Hiperplasia suprarrenal congénita con crisis salina en un recién nacido

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