ESPEYB19 1. Pituitary and Neuroendocrinology Genetics (5 abstracts)
1.5. Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism
Schänzer A , Achleitner MT , Trümbach D , Hubert L , Munnich A , Ahlemeyer B , AlAbdulrahim MM , Greif PA , Vosberg S , Hummer B , Feichtinger RG , Mayr JA , Wortmann SB , Aichner H , Rudnik-Schöneborn S , Ruiz A , Gabau E , Sánchez JP , Ellard S , Homfray T , Stals KL , Wurst W , Neubauer BA , Acker T , Bohlander SK , Asensio C , Besmond C , Alkuraya FS , AlSayed MD , Hahn A & Weber A
Ann Neurol. 2021 Jul;90(1):143-158. doi: 10.1002/ana.26127. PMID: 33999436.
Brief Summary: This study identifies biallelic HID1 variants in 7 patients with hypopituitarism and infantile encephalopathy. It provides genetic and functional evidence for a novel gene-disease connection and expands the list of central nervous system diseases caused by impairment of the trans-Golgi network.
The authors describe 7 infants, 3 of whom had sadly died, with developmental delay, seizures, thin corpus callosum, brain atrophy, and hypopituitarism. The authors used whole exome sequencing to reveal the genetic cause and discovered that every patient harbored segregating, biallelic HID1 variants. The variants were either missense and likely pathogenic (according to the American College of Medical Genetics (ACMG) criteria), frameshifts leading to a premature STOP codon, or located at a splice site. One of the variants was shown to reduce the extracellular acidification rate upon potassium chloride stimulation, which indicated impaired function of the trans-Golgi network.
The trans-Golgi network and HID1 (HID1 domain containing) are closely connected, for HID1 participates in the formation of neuropeptide- and peptide hormone-loaded vesicles via acidification of the network, a vital step for the secretion of the loads (1-3). They demonstrated the highest expression of HID1 in the brain and secretory tissues, especially in the pituitary in humans, and an increase in the brain expression with gestational age. They thus speculated that HID1 could play a role in brain development and the function of the neuronal and secretory cells. In fact, HID1 has been previously proposed to be a candidate gene for syndromic hypopituitarism (4), but no functional evidence on its connection to this phenotype had been provided.
In summary, these findings suggest that HID1 variants underlie a severe form of syndromic hypopituitarism, and that defects in this gene should be considered in the molecular genetic diagnosis of cases with early infantile encephalopathy and multiple pituitary hormone deficiencies.
References: 1. Hummer BH, de Leeuw NF, Burns C, Chen L, Joens MS, Hosford B, Fitzpatrick JAJ, Asensio CS. HID-1 controls formation of large dense core vesicles by influencing cargo sorting and trans-Golgi network acidification. Mol Biol Cell 2017 28(26):3870-3880. 2. Mesa R, Luo S, Hoover CM, Miller K, Minniti A, Inestrosa N, Nonet ML. HID-1, a new component of the peptidergic signaling pathway. Genetics 2011 187(2):467-48. 3. Yu Y, Wang L, Jiu Y, Zhan Y, Liu L, Xia Z, Song E, Xu P, Xu T. HID-1 is a novel player in the regulation of neuropeptide sorting. Biochem J 2011 434(3):383-390. 4. Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al Saud BK, Kurdi W, Makhseed N, Alqasim T, El Khashab HY, Al-Mousa H, Alhashem A, Kanaan I, Algoufi T, Alsaleem K, Basha TA, Al-Murshedi F, Khan S, Al-Kindy A, Alnemer M, Al-Hajjar S, Alyamani S, Aldhekri H, Al-Mehaidib A, Arnaout R, Dabbagh O, Shagrani M, Broering D, Tulbah M, Alqassmi A, Almugbel M, AlQuaiz M, Alsaman A, Al-Thihli K, Sulaiman RA, Al-Dekhail W, Alsaegh A, Bashiri FA, Qari A, Alhomadi S, Alkuraya H, Alsebayel M, Hamad MH, Szonyi L, Abaalkhail F, Al-Mayouf SM, Almojalli H, Alqadi KS, Elsiesy H, Shuaib TM, Seidahmed MZ, Abosoudah I, Akleh H, AlGhonaium A, Alkharfy TM, Al Mutairi F, Eyaid W, Alshanbary A, Sheikh FR, Alsohaibani FI, Alsonbul A, Al Tala S, Balkhy S, Bassiouni R, Alenizi AS, Hussein MH, Hassan S, Khalil M, Tabarki B, Alshahwan S, Oshi A, Sabr Y, Alsaadoun S, Salih MA, Mohamed S, Sultana H, Tamim A, El-Haj M, Alshahrani S, Bubshait DK, Alfadhel M, Faquih T, El-Kalioby M, Subhani S, Shah Z, Moghrabi N, Meyer BF, Alkuraya FS. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet 2017 136(8):921-939.
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ESPE Yearbook of Paediatric Endocrinology
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