WDR62 – Autosomal Recessive Primary Microcephaly

WDR62 encodes a WD repeat–containing scaffold protein critical for neural progenitor mitosis. Biallelic mutations in WDR62 underlie autosomal recessive primary microcephaly (MCPH2), characterized by congenital microcephaly, intellectual disability, and variable cortical malformations. WDR62 localizes to centrosomes, Golgi and spindle poles, coordinating mitotic progression in neural precursors (PMID:20890278).

Genetic evidence supports an autosomal recessive inheritance mode. A representative homozygous deletion c.1143delA (p.His381ProfsTer48) was identified in a five-generation Pakistani family with three affected individuals presenting microcephaly, corpus callosum hypoplasia, schizencephaly and intellectual disability (PMID:23065275). Numerous additional reports describe compound heterozygous frameshift, missense and splice variants in German, East Asian, North African and Saudi families, confirming allelic heterogeneity and founder effects in consanguineous populations (PMID:24228726; PMID:31788460).

Segregation analyses in over 10 unrelated families demonstrate perfect cosegregation of WDR62 variants with MCPH2. Across these cohorts, more than 20 probands and at least 7 additional affected relatives have been documented with biallelic WDR62 lesions, strengthening causality (PMID:23065275; PMID:24228726).

Functional studies reveal loss-of-function as the pathogenic mechanism. Patient-derived cells and animal models show WDR62 mislocalization, spindle instability, activation of the spindle assembly checkpoint, mitotic arrest and apoptosis of neural progenitors. WDR62 interacts with JNK1 and Aurora kinases to regulate spindle dynamics and neurogenesis; rescue experiments with wild-type WDR62 or JNK1 restore normal mitosis (PMID:37272619; PMID:24388750).

No studies have refuted the association or described WDR62 variants in unaffected controls. The concordance between genetic segregation and experimental phenotypes over 14 years of research establishes a definitive gene–disease relationship.

Key Take-home: Biallelic loss-of-function variants in WDR62 cause autosomal recessive primary microcephaly through disruption of centrosome/spindle pole function, supporting its use in molecular diagnosis, genetic counseling and future therapeutic targeting.

References

• Nature genetics • 2010 • Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. PMID:20890278
• Molecular biology reports • 2013 • A novel WDR62 mutation causes primary microcephaly in a Pakistani family. PMID:23065275
• Orphanet journal of rare diseases • 2013 • Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation. PMID:24228726
• Frontiers in pediatrics • 2019 • Two Novel Mutations (c.883-4_890del and c.1684C>G) of WDR62 Gene Associated With Autosomal Recessive Primary Microcephaly: A Case Report. PMID:31788460
• eLife • 2023 • Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors. PMID:37272619

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