Prr12, or Proline Rich 12, is a gene of unknown function with suspected DNA-binding activity [1,6]. It is expressed in developing mouse and human brains, suggesting its importance in brain development [1,6]. In zebrafish, its orthologs prr12a and prr12b have distinct expression patterns during development, mainly in the central nervous system and retina, indicating a potential role in eye and brain development [3]. It has also been identified as a mediator of cohesin and genome integrity, interacting with NIPBL/MAU2 and the cohesin complex [4].

Loss-of-function variants in PRR12 are extremely rare, indicating high intolerance of haploinsufficiency [1]. In humans, individuals with such variants often present with a spectrum of disorders. A total of 24 individuals with PRR12 variants were studied, with all showing developmental impairment, 50% having variable structural eye defects (such as anophthalmia, microphthalmia, etc.), 61% having hypotonia, 52% having heart defects, 54% having growth failure, and 35% having kidney anomalies [1]. Some cases also presented with short stature, normal development/cognition, and absence of neuropsychiatric disorders [2]. A Chinese boy with a novel PRR12 variant presented with intellectual disability, short stature, and mild scoliosis, and was diagnosed with attention deficit hyperactivity disorder [5]. Additionally, three patients with de novo loss-of-function mutations in PRR12 had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems [6].

In conclusion, Prr12 plays a crucial role in neurodevelopment and eye development. Its haploinsufficiency can lead to a wide range of multisystem abnormalities, including those related to the nervous system, eyes, heart, growth, and kidneys. The study of Prr12 through human cases with loss-of-function variants provides insights into the gene's function and its association with various disorders [1,2,5,6].

References:

1. Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Bi, Weimin, Balci, Tugce B. 2021. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 1234-1245. doi:10.1038/s41436-021-01129-6. https://pubmed.ncbi.nlm.nih.gov/33824499/

2. Reis, Linda M, Costakos, Deborah, Wheeler, Patricia G, Fung, Simon S M, Semina, Elena V. 2020. Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia. In Clinical genetics, 99, 437-442. doi:10.1111/cge.13897. https://pubmed.ncbi.nlm.nih.gov/33314030/

3. Muscò, Alessia, Martini, Davide, Digregorio, Matteo, Broccoli, Vania, Andreazzoli, Massimiliano. 2024. Shedding a Light on Dark Genes: A Comparative Expression Study of PRR12 Orthologues during Zebrafish Development. In Genes, 15, . doi:10.3390/genes15040492. https://pubmed.ncbi.nlm.nih.gov/38674426/

4. Nguyen, Alexandra L, Smith, Eric M, Cheeseman, Iain M. 2024. Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity. In Developmental cell, 60, 1217-1233.e7. doi:10.1016/j.devcel.2024.12.015. https://pubmed.ncbi.nlm.nih.gov/39742660/

5. Liu, Zhengxia, Ding, Shuxia, Xu, Guangwei, Fang, Chunyan. 2024. Case Report: Identification of a novel PRR12 variant in a Chinese boy with developmental delay and short stature. In Frontiers in pediatrics, 12, 1367131. doi:10.3389/fped.2024.1367131. https://pubmed.ncbi.nlm.nih.gov/38798311/

6. Leduc, Magalie S, Mcguire, Marianne, Madan-Khetarpal, Suneeta, Yang, Yaping, Bi, Weimin. 2018. De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities. In Human genetics, 137, 257-264. doi:10.1007/s00439-018-1877-0. https://pubmed.ncbi.nlm.nih.gov/29556724/