Gene mutation associated with fertility

A mutation in a gene encoding a cell surface receptor disrupts the growth of lymphatic vessels and linked to miscarriage.



Researchers from Saudi, the UK, and the US, discovered a genetic mutation associated with reduced female fertility and miscarriage due to abnormal fluid accumulation in fetal compartments. 

The condition, known as hydrops fetalis, can occur when the mother's immune system destroys the red blood cells in the fetus. This type of hydrops fetalis can be prevented with an injection of anti-D immunoglobulin. However, there are many other causes, such as heart or lung problems, severe anaemia, and genetic or developmental problems associated with impaired growth of lymphatic vessels, most of which result in fetal death. Further understanding of the mechanisms leading to excessive fluid leaving the bloodstream and the fetus’ capacity to manage fluid could guide the development of new treatments or preventive measures. 

“Our discovery arose from [studying the case of] a 22-year-old healthy woman who was referred to the genetics clinic in King Abdulaziz Medical City after experiencing two second-trimester miscarriages due to hydrops fetalis, and one spontaneous miscarriage in the first trimester,” explains KAIMRC’s Fuad Al Mutairi, one of the study’s lead authors. 

Genetic analyses of all the mother’s protein-coding genes (exome), as well as her husband’s revealed that they both carried a mutation due to the deletion of a single amino acid called valine 205. This mutation impairs the ability of the cell receptor  CLR (calcitonin receptor-lie receptor) to interact properly with the helper proteins RAMPs (receptor activity-modifying proteins). This interferes with the normal cellular function.   

Studies in cells showed that mutated CLR failed to reach the cell surface, thus preventing the receptor’s ligand, adrenomedullin, from binding and disrupting normal adrenomedullin-CLR signalling. Interestingly, deletion of either the genes encoding CLR, its partner protein RAMP2, or adrenomedullin in mice caused mid-gestation embryonic death due to disrupted growth of lymphatic vessels, mimicking the hydrops fetalis observed in humans.  

These results not only highlight a novel role for this conserved signalling pathway in the survival of mammals and female reproductive function, but they have also identified three new genes to study in large-scale genetic testing platforms for hydrops fetalis and other developmental vascular malformations. 

“In theory, females carrying the CLR mutation could benefit from therapies that maintain the normal adrenomedullin-CLR signalling,” says Al Mutairi.  

Drugs that selectively target and modulate the interaction of G-protein-coupled receptors with RAMPs have recently been approved for clinical use in the treatment of migraine. This study suggests that similar strategies targeting the CLR-RAMP2-adrenomedullin interaction may hold potential for improving fertility.


  1. Mackie, D.I., Al Mutairi, F., Davis, R.B., Kechele, D.O., Nielsen, N.R. et al. hCAL CRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. JEM 9, 2339–2353 (2018). | article

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