Bi-Allelic Loss-of-Function Variant in MAN1B1 Cause Rafiq Syndrome and Developmental Delay

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Rafiq syndrome (RAFQS) is a rare autosomal recessive disorder classified as congenital disorder of glycosylation type II (CDG-II).
• It is caused by mutations in the MAN1B1 gene, but pathogenic mechanisms are poorly understood.
• 24 pathogenic MAN1B1 mutations have been reported, highlighting the need for further investigation.

Purpose of the Study:

• To identify the genetic cause of RAFQS in a consanguineous Pakistani family.
• To elucidate the pathogenic mechanisms underlying MAN1B1-related neurodevelopmental deficits.
• To investigate the role of MAN1B1 in human brain development.

Main Methods:

• Exome sequencing and homozygosity mapping to identify novel MAN1B1 mutation.
• Analysis of public single-cell transcriptomic data for MAN1B1 expression patterns.
• In vitro studies using primary mouse neuronal cultures and in utero electroporation in murine models.

Main Results:

• A novel MAN1B1 mutation (c.772_775del) was identified and co-segregated with RAFQS in the family.
• MAN1B1 is predominantly expressed in dorsal progenitors and intermediate excitatory neurons during human brain development.
• MAN1B1 knockdown in mice disrupted neural stem cell proliferation, differentiation, cortical neuron migration, and neuronal development.

Conclusions:

• Loss-of-function mutations in MAN1B1 are critical in the etiology of Rafiq syndrome.
• MAN1B1 plays a vital role in neurodevelopmental processes, including neural stem cell function and neuronal maturation.
• These findings provide mechanistic insights into the pathogenesis of MAN1B1-CDG.