Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Robert, Karine; Maurin, Nicole; Ledru, Aurélie; Delabar, Jean Maurice; Janel, Nathalie

doi:10.1002/ar.a.20082

Cited by 26 publications

(21 citation statements)

References 20 publications

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“…Facial alopecia is the most striking phenotype of Cbs −/− mice on RD, occurring between 105–120 days of age in both males and females (Robert et al 2004; Gupta and Kruger 2011). Previously, we have shown that MRD completely eliminated the facial alopecia phenotype in Cbs −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Gupta

Wang

Kruger

2015

J of Inher Metab Disea

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Cystathionine beta synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Betaine supplementation, which can lower tHcy by stimulating homocysteine remethylation to methionine, is often given to CBS deficient patients in combination with other treatments such as methionine restriction and supplemental B-vitamins. However, the effectiveness of betaine supplementation by itself in the treatment of CBS deficiency has not been well explored. Here, we have examined the effect of a betaine supplemented diet on the TgI278T Cbs−/− mouse model of CBS deficiency and compared its effectiveness to our previously published data using a methionine restricted diet. TgI278T Cbs−/− mice on betaine, from the time of weaning until for 240 days of age, had a 40% decrease in mean tHcy level and a 137% increase in serum methionine levels. Betaine-treated Tg-I278T Cbs−/− mice also exhibited increased levels of betaine-dependent homocysteine methyl transferase (BHMT), increased levels of the lipogenic enzyme stearoyl-coenzyme A desaturase (SCD-1), and increased lipid droplet accumulation in the liver. Betaine supplementation largely reversed the hair loss phenotype in Tg-I278T Cbs−/− animals, but was far less effective than methionine restriction in reversing the weight-loss, fat-loss, and osteoporosis phenotypes. Surprisingly, betaine supplementation had several negative effects in control Tg-I278T Cbs+/− mice including decreased weight gain, lean mass, and bone mineral density. Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective as methionine restriction for reversing the phenotypes associated with severe CBS deficiency in mice.

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Section: Resultsmentioning

confidence: 99%

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Gupta

Wang

Kruger

2015

J of Inher Metab Disea

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“…Moreover, some patients with homocystinuria have other skin abnormalities, such as hypopigmentation (129). Similarly, cbs Ϫ/Ϫ mice have hyperkeratosis, wrinkled skin, and an abnormally thin dermal layer (134). Fibrosis and collagen disruption have also been reported in other studies using various tissues from CBS-deficient mice, and this phenotype is not tissue specific.…”

Section: Skin and Skeletal Phenotypes Of Cbs Deficiencymentioning

confidence: 94%

Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Beard

Bearden

2011

American Journal of Physiology-Heart and Circulatory Physiology

106

110

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Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H(2)S) through the transsulfuration pathway. H(2)S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H(2)S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (-/-) and heterozygous (+/-), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H(2)S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.

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“…Knockout mouse pathogenesis CBS [137][138][139][140] Hyperhomocysteinemia Hyperkeratosis MAT1A 89 Spontaneous hepatocellular carcinoma and impaired liver regeneration MTHFR 85,141 Hyperhomocysteinemia (À/+ and À/À) Developmental retardation with cerebellar pathology (À/À) Aortic lipid deposition (À/+ and À/À) Abnormal spermatogenesis (À/À) FOLR1 (Folbp1 Embryonic lethality (À/À) mouse homolog) 90 reversed by folinic acid supplementation of (À/+) dams…”

Section: Genementioning

confidence: 99%

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

2009

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Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Cited by 26 publications

References 20 publications

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice

Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

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