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.8,9

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, 10-14

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, 10-14

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:15-18

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 available19

Patterns of inheritance20

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, comprehensive 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 2021.

Gene symbol or region (alternate) OMIM ID
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
C8ORF37 (BBS21) 614477
CEP290 (BBS14) 610142
CPE 114855
CREBBP 600140
CUL4B 300304
DNMT3A 602769
DYRK1B 604556
EP300 602700
GNAS 139320
HTR2C 312861
IFT172 607386
IFT27 (BBS19) 615870
IFT74 (BBS20) 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
Recognizing potential cases
Gene symbol or region (alternate) OMIM ID
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 601665
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
Gene symbol or region (alternate) OMIM ID
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
C8ORF37 (BBS21) 614477
CEP290 (BBS14) 610142
CPE 114855
CREBBP 600140
CUL4B 300304
DNMT3A 602769
DYRK1B 604556
EP300 602700
GNAS 139320
HTR2C 312861
IFT172 607386
IFT27 (BBS19) 615870
IFT74 (BBS20) 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 601665
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

*Assessment for rearrangement of the 16p11.2 chromosomal region


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.


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