A Balanced Translocation in Kallmann Syndrome Implicates a Long Noncoding RNA, RMST, as a GnRH Neuronal Regulator

Area of Science:

• Genetics
• Developmental Biology
• Endocrinology

Background:

• Kallmann syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism and anosmia.
• Structural defects in KS patients have elucidated the genetic basis of gonadotropin-releasing hormone (GnRH) neuronal development.
• Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in gene regulation and development.

Observation:

• A unique translocation, t(7;12)(q22;q24), was identified in a KS patient, affecting the long noncoding RNA (lncRNA) RMST on chromosome 12.
• Induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient exhibited functional differences compared to controls, specifically concerning RMST expression and NCC morphology.

Findings:

• RMST expression was substantially reduced in the KS patient's NCC during differentiation, contrasting with increased expression in controls, leading to abrogated NCC morphological development.
• Abnormal expression of key developmental genes (SOX2, PAX3, CHD7, TUBB3, MKRN3) essential for GnRH ontogeny was observed in the patient's NCC.
• A single nucleotide polymorphism within RMST was significantly associated with the age of menarche in a genome-wide association study.

Implications:

• The loss of function of the RMST lncRNA is implicated as a novel cause of Kallmann syndrome, highlighting its critical role in GnRH neuron development and puberty.
• This study expands the genetic landscape of KS and underscores the importance of lncRNAs in human reproductive health and neurodevelopment.