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Updated: Jan 13, 2026

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The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial

Linjuan Yuan1, Shanshan Cheng1, Xian Liu1

  • 1School of Life Science and Technology, the Key Laboratory of Developmental Genes and Human Disease, Southeast University, 2 Dongda Road, Nanjing, China.

Nature Communications
|January 8, 2026
PubMed

Insights

The Y65C mutation in polyglutamine-binding protein 1 (PQBP1) causes Renpenning syndrome by impairing brain development. This study reveals dual loss-of-function and gain-of-function mechanisms driving microcephaly and cognitive deficits.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Renpenning syndrome is an X-linked disorder featuring intellectual disability and microcephaly.
  • The precise molecular mechanisms driving Y65C-induced microcephaly in polyglutamine-binding protein 1 (PQBP1) mutations are not fully understood.

Purpose of the Study:

  • To investigate the pathogenic mechanisms of the PQBP1 Y65C mutation associated with Renpenning syndrome.
  • To elucidate how this mutation impacts progenitor cell proliferation and brain development.

Main Methods:

  • Generation of Pqbp1Y65C/Y knock-in male mice.
  • Analysis of apical and basal progenitor cell proliferation and differentiation.
  • Investigation of PQBP1 protein levels and interactions with mRNA processing machinery.

Main Results:

  • The Y65C mutation impairs apical progenitor proliferation and the transition to basal progenitors, causing microcephaly and cognitive deficits.
  • PQBP1 misfolding due to Y65C reduces protein levels, hindering progenitor proliferation (loss-of-function).
  • The Y65C mutation enhances interactions with mRNA 3' end processing, preserving proliferative APA profiles (gain-of-function).

Conclusions:

  • The Y65C mutation in PQBP1 contributes to Renpenning syndrome through a dual mechanism of loss-of-function and gain-of-function.
  • These mechanisms disrupt neural progenitor cell dynamics, leading to microcephaly and intellectual disability.

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