A closer look at the MC4R pathway

The melanocortin-4 receptor (MC4R) pathway plays a critical role in maintaining a healthy body weight.

Signaling along this pathway regulates hunger, satiety, and energy expenditure, all of which can influence body weight.9,10

Explore the impact of the MC4R Pathway in Bardet-Biedl syndrome (BBS)

MC4R pathway
Functional pathway signaling the hypothalamus in response to leptin release to signify satiety Functional pathway signaling the hypothalamus in response to leptin release to signify satiety

Functional pathway signaling

The MC4R pathway plays a key role in regulating hunger, which involves neural activation within the hypothalamic region of the brain in response to leptin release from adipose tissue. Proper regulation of hunger requires sufficient levels of melanocyte-stimulating hormone (MSH) neuropeptides that activate MC4R, triggering a reduction in hunger and concomitant increase in energy expenditure.1,11-15

Functional pathway signaling the hypothalamus in response to leptin release to signify satiety
Impaired MC4R pathway may result in hyperphagia and weight gain Impaired MC4R pathway may result in hyperphagia and weight gain

Impaired pathway signaling

Genetic variants within the MC4R pathway may result in rare genetic diseases of obesity.

In patients with rare genetic diseases of obesity, MC4R pathway signaling is impaired due to genetic variants upstream of the MC4 receptor, leading to early-onset, severe obesity and hyperphagia.1,11-15

Impaired MC4R pathway may result in hyperphagia and weight gain

Explore common signs

Distinct from general obesity cases, rare genetic diseases of obesity can be non-syndromic (e.g., POMC or LEPR deficiency) or syndromic (e.g., Bardet-Biedl syndrome or Alström syndrome).

The role of genetic variants

Genetic testing can help reveal disease-causing genetic variants. The American College of Medical Genetics and Genomics classifies variants into 5 categories, as follows:16-19

Pathogenic

Can be used in clinical decision-making

Likely Pathogenic

Can be used in decision-making when combined with other evidence of the disease in question

Variant of Uncertain Significance (VUS)

Because ACMG guidelines recommend a finding of a VUS not be used in clinical decision-making, the management and clinical diagnosis of a patient with a VUS should be based on clinical judgment and patient history

Benign*

Can conclude the variant is not the cause of the disease

Likely Benign*

Can conclude the variant is not the cause of the disease when combined with other evidence

*often reported as negative

  • Benign and likely benign variants are generally not included in a diagnostic report
  • If a VUS is identified, efforts by the testing laboratory may be taken to resolve the classification as pathogenic or benign as new information becomes available20

Patterns of inheritance21

Rare genetic diseases of obesity are inherited in several patterns, depending on the gene involved and whether the related genotype is dominant or recessive.

Learn about inheritance of BBS

In autosomal recessive inheritance

  • 2 copies of variant allele are required for the phenotype to be present (e.g., homozygous or compound heterozygous variants are required)
  • Both parents of the affected individual are likely carriers of a single variant
  • Not typically observed in every generation

Biallelic Genotypes

Patterns of inheritance biallelic genotypes

In autosomal dominant inheritance

  • 1 copy of the allele is sufficient for the phenotype to be present (e.g., heterozygous variants are sufficient)
  • The affected individual likely has 1 affected parent
  • Disease can occur in every generation

Heterozygous Genotypes

Patterns of inheritance other heterozygous genotypes

Biallelic Genotypes

Patterns of inheritance biallelic genotypes

Heterozygous Genotypes

Patterns of inheritance other heterozygous genotypes

Rhythm Pharmaceuticals offers a no-charge genetic testing program for rare genetic diseases of obesity. The genes and chromosome region included in the test are listed below and are also available here.

Gene or region symbols may change and are current as of October 2024.

Gene Symbol or Region (alternate*) OMIM
Gene Number
ADCY3 600291
AFF4 604417
ALMS1 606844
ARL6 (BBS3) 608845
ASIP 600201
BBIP1 (BBS18) 613605
BBS10 610148
BBS12 610683
BBS1 209901
BBS2 606151
BBS4 600374
BBS5 603650
BBS7 607590
BBS9 (PTHB1) 607968
BDNF 113505
CFAP418 (BBS21) 614477
CEP164 614848
CEP290 (BBS14) 610142
CPE 114855
CREBBP 600140
CUL4B 300304
DNMT3A 602769
DYRK1B 604556
EP300 602700
GNAS 139320
HTR2C 312861
IFT172 (BBS20) 607386
IFT27 (BBS19) 615870
IFT74 (BBS22) 608040
INPP5E 613037
Recognizing potential cases
Gene Symbol or Region (alternate*) OMIM
Gene Number
ISL1 600366
KIDINS220 615759
KSR2 610737
LEP 164160
LEPR 601007
LRRC45
LZTFL1 (BBS17) 606568
MAGEL2 605283
MC3R 155540
MC4R 155541
MECP2 300005
MKKS (BBS6) 604896
MKS1 (BBS13) 609883
MRAP2 615410
NCOA1 (SRC1) 602691
NPHP1 607100
NR0B2 604630
NRP1 602069
NRP2 602070
NTRK2 600456
PCNT 605925
PCSK1 162150
PHF6 300414
PHIP 612870
PLXNA1 601055
PLXNA2 601054
PLXNA3 300022
PLXNA4 604280
POMC 176830
PPARG 601487
Gene Symbol or Region (alternate*) OMIM
Gene Number
PROK2 607002
RAB23 606144
RAI1 607642
RPGRIP1L 610937
RPS6KA3 300075
SCAPER 611611
SCLT1 611399
SDCCAG8 (BBS16) 613524
SEMA3A 603961
SEMA3B 601281
SEMA3C 602645
SEMA3D 609907
SEMA3E 608166
SEMA3F 601124
SEMA3G
SH2B1 608937
SIM1 603128
TBX3 601621
TMEM67 609884
TRIM32 (BBS11) 602290
TRPC5 300334
TTC8 (BBS8) 608132
TTC21B 612014
TUB 601197
UCP3 602044
VPS13B 607817
WDPCP (BBS15) 613580
16p11.2 chromosomal region† 611913‡
Download the gene panel pdf
Gene Symbol or Region (alternate*) OMIM
Gene Number
ADCY3 600291
AFF4 604417
ALMS1 606844
ARL6 (BBS3) 608845
BBIP1 (BBS18) 613605
BBS10 610148
BBS12 610683
BBS1 209901
BBS2 606151
BBS4 600374
BBS5 603650
BBS7 607590
BBS9 (PTHB1) 607968
BDNF 113505
CFAP418 (BBS21) 614477
CEP290 (BBS14) 610142
CPE 114855
CREBBP 600140
CUL4B 300304
DNMT3A 602769
DYRK1B 604556
EP300 602700
GNAS 139320
HTR2C 312861
IFT172 (BBS20) 607386
IFT27 (BBS19) 615870
IFT74 (BBS22) 608040
INPP5E 613037
ISL1 600366
KIDINS220 615759
KSR2 610737
LEP 164160
LEPR 601007
LZTFL1 (BBS17) 606568
MAGEL2 605283
MC3R 155540
MC4R 155541
MECP2 300005
MKKS (BBS6) 604896
MKS1 (BBS13) 609883
MRAP2 615410
NCOA1 (SRC1) 602691
NR0B2 604630
NRP1 602069
NRP2 602070
NTRK2 600456
PCNT 605925
PCSK1 162150
PHF6 300414
PHIP 612870
PLXNA1 601055
PLXNA2 601054
PLXNA3 300022
PLXNA4 604280
POMC 176830
PPARG 601487
PROK2 607002
RAB23 606144
RAI1 607642
RPGRIP1L 610937
RPS6KA3 300075
SDCCAG8 (BBS16) 613524
SEMA3A 603961
SEMA3B 601281
SEMA3C 602645
SEMA3D 609907
SEMA3E 608166
SEMA3F 601124
SEMA3G
SH2B1 608937
SIM1 603128
TBX3 601621
TRIM32 (BBS11) 602290
TRPC5 300334
TTC8 (BBS8) 608132
TUB 601197
UCP3 602044
VPS13B 607817
WDPCP (BBS15) 613580
16p11.2 chromosomal region† 611913‡
Download the gene panel pdf
Recognizing potential cases

*Alternate gene symbols or phenotype abbreviations listed for clarity.
†Assessment for rearrangement of the 16p11.2 chromosomal region.
‡OMIM phenotype number.
Gene symbols and alternative names may change and are current as of October 2024.

ALMS1=Alström syndrome 1; LEPR=leptin receptor; PCSK1=proprotein convertase subtilisin/kexin type 1; POMC=proopiomelanocortin; SH2B1=SH2B adaptor protein 1; SRC1=steroid receptor coactivator-1.

  • References

    1. Huvenne H, Duberne B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9(3):158-173.

    2. Ellacott KL, Cone RD. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Land B Biol Sci. 2006;361(1471):1265-1274.

    3. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age,
      2007-2008 to 2015-2016. JAMA. 2018;319(16):1723-1725.

    4. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013;8(5):e64-e67.

    5. Ward ZJ, Long MW, Resch SC, Giles CM, Cradock AL, Gortmaker SL. Simulation of growth trajectories of childhood obesity into adulthood. N Engl J Med.
      2017;377(22):2145-2153.

    6. Data on file. Rhythm Pharmaceuticals, Inc. Boston, MA.

    7. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin
      Endocrinol Metab. 2017;102(3);709-757.

    8. Cuda S, Censani M, O’Hara V, et al. Pediatric Obesity Algorithm eBook. Obesity Medicine Association. 2020-2022.
      http://www.obesitymedicine.org/childhood-obesity. Accessed June 8, 2021.

    9. Morton GJ, Meek TH, Schwartz MW. Neurobiology of food intake in health and disease. Nat Rev Neurosci. 2014;15(6):367-378.

    10. van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161(1):119-132.

    11. da Fonseca ACP, Mastronardi C, Johar A, Arcos-Burgos M, Paz-Filho G. Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies. J Diabetes Complications. 2017;31(10):1549-1561.

    12. Yazdi FT, Clee SM, Meyre D. Obesity genetics in mouse and human: back and forth, and back again. PeerJ. 2015;3:e856.

    13. Burns B, Schmidt K, Williams SR, Kim S, Girirajan S, Elsea SH. Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Hum Mol Genet. 2010;19(20):4026-4042.

    14. Lu Q, Yang Y, Jia S, et al. SRC1 deficiency in hypothalamic arcuate nucleus increases appetite and body weight. J Mol Endocrinol. 2018:JME-18-0075.R2.

    15. Vaisse C, Reiter JF, Berbari NF. Cilia and obesity. Cold Spring Harb Perspect Biol. 2017;9(7):a028217.

    16. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-424.

    17. Sequencing Sample Reports: Indeterminate (with CNV). Prevention Genetics. Updated October 18, 2009. https://www.preventiongenetics.com/ClinicalTesting/TestCategory/sampleReports. Accessed November 11, 2021.

    18. A guide to understanding variant classification. Blueprint Genetics. https://blueprintgenetics.com/wp-content/uploads/2020/10/Variant_Classification_WP_VARA41-06-FINAL.pdf. Accessed November 11, 2021

    19. VUS – the most maligned result in genetic testing. Blueprint Genetics. Updated October 29, 2020. https://blueprintgenetics.com/resources/vus-the-most-maligned-result-in-genetic-testing/. Accessed November 11, 2021.

    20. Bean LJH, Tinker SW, da Silva C, Hegde MR. Free the data: one laboratory’s approach to knowledge-based genomic variants classification and preparation for EMR integration of genomic data. Hum Mutat. 2013;34:1183-1188.

    21. Online Mendelian Inheritance in Man. Entries 609734, 600955, and 614963. https://www.omim.org/. Accessed November 18, 2021.

    22. Kohlsdorf K, Nunziata A, Funcke JB, et al. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency. Int J Obes (Lond). 2018;42(9):1602-1609.

    23. Heymsfield SB, Avena NM, Baier L, et al. Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring). 2014;22 Suppl 1(0 1):S1-S17.

    24. Shah BP, Moeller IH, Van der Ploeg LHT, Garfield AS. Identification and functional characterization of novel variants in genes in the MC4R pathway associated with severe early-onset obesity and hyperphagia. Oral presentation at: Keystone Symposia. February 2019. Banff, Alberta, Canada.

    25. Rhythm 10-K Annual Report (2020). Rhythm Pharmaceuticals. Accessed November 11, 2021.

    26. Rhythm 10-K Annual Report (2024). Rhythm Pharmaceuticals. Accessed March 15, 2024.

    27. Ayers KL, Glicksberg BS, Garfield AS, et al. Melanocortin 4 Receptor pathway dysfunction in obesity: patient stratification aimed at MC4R agonist treatment. J Clin Endocrinol Metab. 2018;103:2601-2612.

    28. Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet-Biedl syndrome—now and in the future. Front Pediatr. 2018;6:23.

    29. Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21(1):8-13.

    30. Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond). 2016;130(12):943-986.

    31. Joy T, Cao H, Black G, et al. Alström syndrome (OMIM 203800): a case report and literature review. Orphanet J Rare Dis. 2007;2:49.

    32. Van Groenendael S, Giacovazzi L, Davison F, et al. High quality, patient centred and coordinated care for Alstrom syndrome: a model of care for an ultra-rare disease. Orphanet J Rare Dis. 2015;10:149.

    33. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26:1039.

    34. Paisey RB, Steeds R, Barrett T, et al. Alström Syndrome. GeneReviews®. February 7, 2003. Updated June 13, 2019. https://www.ncbi.nlm.nih.gov/books/NBK1267/. Accessed November 10, 2021.

    35. Coll AP, Farooqi SI, Challis BG, Yeo GSH, O’Rahilly S. Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinal Metab. 2004,89:2557.

    36. Mendiratta MS, Yang Y, Balazs AE, et al. Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinal. 2011;5.

    37. National Institutes of Health. POMC deficiency. MedlinePlus®. Updated August 18, 2020. https://medlineplus.gov/genetics/condition/proopiomelanocortin-deficiency/. Accessed November 10, 2021.

    38. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237.

    39. Stijnen P, Ramos-Molina B, O’Rahilly S, et al. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorder. Endocr Rev. 2016;37(4):347-371.

    40. Martin MG, Lindberg I, Solorzano-Vargas RS, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145(1):138-148.

    41. Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes. 2014;5:511.

    42. Doche ME, Bochukova EG, Su HW, et al. Human SH2B1 mutations are associated with maladaptive behaviors and obesity. J Clin Invest. 2012;122:4732.

    43. Yang Y, van der Klaauw AA, Zhu L, et al. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nat Commun. 2019;10:1718.

    44. Cacciottolo TM, Perikari A, van der Klaauw A, et al. Rare variants in Steroid Receptor Coactivator-1 (SRC-1) associated with obesity, adipose tissue dysfunction and liver fibrosis. QJM. 2019;112(9);724-729.

    45. National Institutes of Health. Bardet-Biedl syndrome. MedlinePlus®. Updated August 18, 2020. https://medlineplus.gov/genetics/condition/bardet-biedl-syndrome/#inheritance. Accessed June 15, 2021.

    46. Pomeroy J, Krentz AD, Richardson JG, et al. Bardet-Biedl syndrome. Pediatr Obes. 2021;16:e12703.

    47. Forsythe E, Sparks K, Hoskins BE, et al. Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome. Clin Genet. 2015;87(4):343-349.

    48. Vos N, Oussaada S, Cooiman MI, et al. Bariatric surgery for monogenic non-syndromic and syndromic obesity disorder. Curr Diab Rep. 2020;20(44):1-10.

    49. Kenny J, Forsythe E, Beales P, Bacchelli C. Toward personalized medicine in Bardet-Biedl syndrome. Per Med. 2017;14(5):447-456.

    50. Poitou C, Mosbah H, Clement K. Mechanisms in endocrinology: update on treatments for patients with genetic obesity. Eur J Endocrinol. 2020;183(5):R149-R166.

    51. Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol. 2018;14(1):12-24.

    52. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437-446.

    53. Forsyth R, Gunay-Aygun M. Bardet-Biedl syndrome overview. GeneReviews®. July 14, 2003. Updated July 23, 2020. https://www.ncbi.nlm.nih.gov/books/NBK1363/. Accessed November 10, 2021.

    54. Alvarez-Satta M, Castro-Sanchez C, Valverde D. Alström syndrome: current perspectives. Appl Clin Genet. 2015;8:171-179.

    55. Nordang GBN, Busk OL, Tveten K, et al. Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls. Mol Genet Metab. 2017;121:51.

    56. Aliferis K, Helle S, Gyapay G, et al. Differentiating Alström from Bardet-Biedl syndrome (BBS) using systemic ciliopathy genes sequencing. Ophthalmic Genet. 2012;33(1): 18-22.

    57. Eneli I, Xu J, Webster M, et al. Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry. Appl Clin Genet. 2019;12:87-93.

    58. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-1331.

    59. Courbage S, Poitou S, Le Beyec – Le Bihan J, et al. Implication of heterozygous variants in genes of the leptin-melanocortin pathway in severe obesity. J Clin Endocrinol Metab. 2021;106(10):2991-3006.