CEP135 – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by reduced head circumference at birth, nonprogressive intellectual disability, and a structurally normal but smaller cerebral cortex. The centrosomal protein CEP135 (HGNC:29086) has been implicated in neurogenic mitosis, where its loss disrupts spindle orientation and neuronal precursor proliferation, leading to microcephaly. CEP135 and Autosomal Recessive Primary Microcephaly association has been investigated through genetic and functional studies.

In 2012, homozygous truncating variants in CEP135 were identified in a consanguineous Pakistani family with two siblings presenting primary microcephaly (2 probands) segregating with a single-gene defect (PMID:22521416). Linkage and sequencing analysis pinpointed a c.2764C>T (p.Arg922Ter) variant in CEP135, absent in unaffected relatives and controls, consistent with an autosomal recessive inheritance pattern.

The affected individuals exhibited birth‐onset microcephaly (head circumference ≥4 SD below the mean) and intellectual disability without cortical malformations. MRI demonstrated reduced brain volume with intact architecture. The c.2764C>T (p.Arg922Ter) allele truncates the C-terminal coiled-coil domain essential for centrosome stability and has not been reported recurrently in other populations.

Variant spectrum in CEP135 associated with autosomal recessive primary microcephaly comprises multiple loss‐of‐function alleles including nonsense (e.g., c.2764C>T), frameshift, and splice-site mutations (PMID:22521416). No founder variants have been described to date, and available carrier frequencies remain below 0.01% in population databases.

Functional assays in patient-derived fibroblasts revealed multiple and fragmented centrosomes, disorganized microtubules, and reduced proliferation rate. RNA interference of CEP135 and ectopic expression of the mutant protein recapitulated these defects, establishing a loss-of-function mechanism. Structural studies of the N-terminal 158 residues defined a parallel two-stranded coiled-coil domain that mediates microtubule binding and bundling, further underscoring the role of CEP135 in centrosomal microtubule organization (PMID:27477386).

Overall, biallelic loss-of-function variants in CEP135 disrupt centrosome integrity and mitotic spindle dynamics, causing autosomal recessive primary microcephaly. This Moderate association is supported by one multiplex family (2 probands) with segregation and concordant functional data. CEP135 should be included in diagnostic gene panels for primary microcephaly to facilitate molecular diagnosis, carrier testing, and genetic counseling.

References

• American Journal of Human Genetics • 2012 • A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. PMID:22521416
• Structure (London, England : 1993) • 2016 • The Human Centriolar Protein CEP135 Contains a Two-Stranded Coiled-Coil Domain Critical for Microtubule Binding. PMID:27477386

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