Additional rare genetic diseases
of obesity

  • SRC1 deficiency

    Steroid receptor coactivator-1 (SRC1) deficiency is a disease caused by variants in the NCOA1 gene, which plays a role in the MC4R pathway6:

    • The NCOA1 gene encodes for the transcriptional coactivator SRC1
    • SRC1 signaling is required for proper leptin signaling
    • The SRC1 protein modulates the expression of POMC

    Inheritance

    SRC1 deficiency is inherited in an autosomal dominant* manner.7,43

    *Dysfunction/loss of only one copy of the NCOA1 gene is sufficient to give rise to obesity and hyperphagia.6

    Diagnosis

    Diagnosis of SRC1 deficiency may be suspected by clinical presentation of the disease and confirmed via genetic testing.

    Common Features6,14,43,44

    Early onset obesity

    Early-onset severe obesity

    Hyperphagia

    Hyperphagia

    Hyperleptinemia

    Hyperleptinemia

    Hyperinsulinemia and insulin resistance

    Hyperinsulinemia and insulin resistance

    Diagnosis

    Diagnosis of SRC1 deficiency may be suspected by clinical presentation of the disease and confirmed via genetic testing.

  • SH2B1 deficiency

    SH2B adaptor protein 1 (SH2B1) deficiency is a disease caused by variants in the SH2B1 gene and 16p11.2 chromosomal deletions, which both play a role in the MC4R pathway6:

    • The SH2B1 gene encodes for the adaptor protein SH2B1
    • SH2B1 enhances activation of LEPR downstream signaling pathways through JAK2 activation
    • Impaired SH2B1 activity/expression leads to insufficient LEPR activity

    Inheritance

    SH2B1 deficiency is inherited in an autosomal dominant† manner.7

    †Dysfunction/loss of only one copy of the SH2B1 gene is sufficient to give rise to obesity and hyperphagia.6

    Diagnosis

    Diagnosis of SH2B1 deficiency may be suspected by clinical presentation of the disease and confirmed via genetic testing.

    Common Features40,41

    Early onset obesity

    Early-onset severe obesity

    Hyperphagia

    Hyperphagia

    Hyperinsulinemia and insulin resistance

    Hyperinsulinemia and insulin resistance

    Reduced final height

    Reduced final height

    Leptin resistance

    Leptin resistance

    Diagnosis

    Diagnosis of SH2B1 deficiency may be suspected by clinical presentation of the disease and confirmed via genetic testing.

JAK=Janus kinase; LEPR=leptin receptor; MC4R=melanocortin-4 receptor; NCOA1=nuclear receptor coactivator 1; POMC=pro-opiomelanocortin.

  • References

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